Publications by authors named "Robert J Slack"

29 Publications

  • Page 1 of 1

Downregulation of the v6 Integrin via RGD Engagement Is Affinity and Time Dependent.

J Pharmacol Exp Ther 2021 02 14;376(2):273-280. Epub 2020 Dec 14.

Fibrosis Discovery Performance Unit (DPU), Respiratory Therapy Area Unit (TAU), GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.

The arginyl-glycinyl-aspartic acid (RGD) integrin alpha-v beta-6 (v6) has been identified as playing a key role in the activation of transforming growth factor- (TGF) that is hypothesized to be pivotal in the development of fibrosis and other diseases. In this study, v6 small molecule inhibitors were characterized in a range of in vitro systems to determine affinity, kinetics, and duration of TGF inhibition. High v6 binding affinity was shown to be correlated with slow dissociation kinetics. Compound (high v6 affinity, slow dissociation) and SC-68448 (low v6 affinity, fast dissociation) induced concentration- and time-dependent internalization of v6 in normal human bronchial epithelial (NHBE) cells. After washout, the v6 cell surface repopulation was faster for SC-68448 compared with compound In addition, v6-dependent release of active TGF from NHBE cells was inhibited by compound and SC-68448. After washout of SC-68448, release of active TGF was restored, whereas after washout of compound the inhibition of TGF activation was maintained and only reversible in the presence of a lysosomal inhibitor (chloroquine). However, SC-68448 was able to reduce total levels of v6 in NHBE cells if present continuously. These observations suggest v6 can be degraded after high affinity RGD binding that sorts the integrin for lysosomal degradation after internalization, likely due to sustained engagement as a result of slow dissociation kinetics. In addition, the v6 integrin can also be downregulated after sustained engagement of the RGD binding site with low affinity ligands that do not sort the integrin for immediate lysosomal degradation. SIGNIFICANCE STATEMENT: The fate of RGD integrin after ligand binding has not been widely investigated. Using the αvβ6 integrin as a case study, we have demonstrated that RGD-induced downregulation of αvβ6 is both affinity and time dependent. High affinity ligands induced downregulation via lysosomal degradation, likely due to slow dissociation, whereas sustained low affinity ligand engagement was only able to decrease αvβ6 expression over longer periods of time. Our study provides a potential unique mechanism for obtaining duration of action for drugs targeting integrins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.120.000379DOI Listing
February 2021

Target-inhibition of Galectin-3 by Inhaled TD139 in Patients with Idiopathic Pulmonary Fibrosis.

Eur Respir J 2020 Nov 19. Epub 2020 Nov 19.

National Institute for Health Research Respiratory Clinical Research Facility, Royal Brompton and Harefield NHS Foundation Trust, and Fibrosis Research Group, National Heart and Lung Institute, Imperial College, London, UK.

Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small molecule inhibitor of Gal-3.A randomised, double-blind, multi-centre, placebo-controlled, phase I/IIa study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF (NCT02257177). Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15 mg to 50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once daily doses of TD139 (0.3 mg to 10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side effects. TD139 was rapidly absorbed, with mean T values ranging from 0.6 h to 3 h and a T of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 mg and 10 mg dose groups compared to placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (PDGF-BB, PAI-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on BAL macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.02559-2020DOI Listing
November 2020

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis.

Nat Commun 2020 09 16;11(1):4659. Epub 2020 Sep 16.

Nordic Bioscience A/S, Biomarkers and Research, Herlev Hovedgade 205-207, Herlev, Denmark.

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18397-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494911PMC
September 2020

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor.

Respir Res 2020 Mar 26;21(1):75. Epub 2020 Mar 26.

GlaxoSmithKline Research and Development, Stevenage, UK.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF.

Methods: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (V), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in V > 0%) of ≥80%.

Results: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected V at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in V > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination.

Conclusions: This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug.

Trial Registration: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12931-020-01339-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099768PMC
March 2020

Preclinical evaluation of [F]FB-A20FMDV2 as a selective marker for measuring αβ integrin occupancy using positron emission tomography in rodent lung.

Eur J Nucl Med Mol Imaging 2020 04 3;47(4):958-966. Epub 2020 Jan 3.

Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.

Purpose: Integrin αβ belongs to the RGD subset of the integrin family, and its expression levels are a prognostic and theranostic factor in some types of cancer and pulmonary fibrosis. This paper describes the GMP radiolabelling of the synthetic 20 amino acid peptide A20FMDV2 (NAVPNLRGDLQVLAQKVART), derived from the foot-and-mouth disease virus, and characterises the use of [F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αβ in rodent lung to support human translational studies.

Methods: The synthesis of [F]FB-A20FMDV2 was performed using a fully automated and GMP-compliant process. Sprague-Dawley rats were used to perform homologous (unlabelled FB-A20FMDV2) and heterologous (anti-αβ antibody 8G6) blocking studies. In order to generate a dosimetry estimate, tissue residence times were generated, and associated tissue exposure and effective dose were calculated using the Organ Level Internal Dose Assessment/Exponential Modelling (OLINDA/EXM) software.

Results: [F]FB-A20FMDV2 synthesis was accomplished in 180 min providing ~800 MBq of [F]FB-A20FMDV2 with a molar activity of up to 150 GBq/μmol and high radiochemical purity (> 97%). Following i.v. administration to rats, [F]FB-A20FMDV2 was rapidly metabolised with intact radiotracer representing 5% of the total radioactivity present in rat plasma at 30 min. For the homologous and heterologous block in rats, lung-to-heart SUV ratios at 30-60 min post-administration of [F]FB-A20FMDV2 were reduced by 38.9 ± 6.9% and 56 ± 19.2% for homologous and heterologous block, respectively. Rodent biodistribution and dosimetry calculations using OLINDA/EXM provided a whole body effective dose in humans 33.5 μSv/MBq.

Conclusion: [F]FB-A20FMDV2 represents a specific and selective PET ligand to measure drug-associated αvβ6 integrin occupancy in lung. The effective dose, extrapolated from rodent data, is in line with typical values for compounds labelled with fluorine-18 and combined with the novel fully automated and GMP-compliant synthesis and allows for clinical use in translational studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-019-04653-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075836PMC
April 2020

Profile of a Highly Selective Quaternized Pyrrolidine Betaine αβ Integrin Inhibitor-(3)-3-(3-(3,5-Dimethyl-1-pyrazol-1-yl)phenyl)-4-((1 and 1,3)-1-methyl-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-ium-1-yl)butanoate Synthesized by Stereoselective Methylation.

J Med Chem 2019 08 5;62(16):7543-7556. Epub 2019 Aug 5.

Department of Pure & Applied Chemistry , University of Strathclyde , 295 Cathedral Street , Glasgow , G1 1XL , U.K.

A quaternary ammonium betaine is described which shows exceptional potency and selectivity (1.4 to >3 logs) for the αβ integrin receptor over the other α integrins as determined in cell adhesion assays. is prepared by remarkably stereoselective methylation, the origins of which are discussed. The chemical, biological, physicochemical, and pharmacokinetic properties of and its docking into αβ are described along with related analogues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b00819DOI Listing
August 2019

The Design of Potent, Selective and Drug-Like RGD αvβ1 Small-Molecule Inhibitors Derived from non-RGD α4β1 Antagonists.

ChemMedChem 2019 07 1;14(14):1315-1320. Epub 2019 Jul 1.

GlaxoSmithKline (GSK), Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK.

Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvβ1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identification of non-RGD hit small-molecule αvβ1 inhibitors. We show that αvβ1 activity is embedded in a range of published α4β1 (VLA-4) ligands; we also demonstrate how a non-RGD integrin inhibitor (of α4β1 in this case) was converted into a potent non-zwitterionic RGD integrin inhibitor (of αvβ1 in this case). We designed urea ligands with excellent selectivity over α4β1 and the other αv integrins (αvβ3, αvβ5, αvβ6, αvβ8). In silico docking models and density functional theory (DFT) calculations aided the discovery of the lead urea series.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.201900359DOI Listing
July 2019

The effect of divalent metal cations on the αv integrin binding site is ligand and integrin specific.

Biomed Pharmacother 2019 Feb 4;110:362-370. Epub 2018 Dec 4.

Fibrosis Discovery Performance Unit, Respiratory TAU, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, UK. Electronic address:

The binding of orthosteric ligands to integrins requires the presence of divalent metal cations bound to metal ion-binding sites located in the I domains of the integrin α and β subunits. In this study the influence of the type and concentration of divalent metal cation present was investigated on a single arginyl-glycinyl-aspartic acid (RGD) ligand across the αv integrin sub-family and single αv integrin (αvβ6) with different ligands. These relationships were determined using radioligand binding studies completed with [H] ligands and purified αv integrin protein preparations. The binding of [H]compound 1 to the RGD site on individual αv integrins demonstrated a unique profile in relation to the type and concentration of divalent metal cation present. The use of physiological concentrations of Mg and Ca in simulated lung fluid altered the αv integrin selectivity profile of [H]compound 1 in terms of affinity and the level of receptor occupancy. In addition, different RGD ligands for the αvβ6 integrin behaved differently under the same divalent metal cation conditions. In conclusion, this study demonstrates the need to determine the individual relationship between RGD ligands and the integrins they may engage in vivo, especially when determining selectivity profiles for potential RGD-mimetic small molecule therapeutics, with organ and disease state also considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2018.11.130DOI Listing
February 2019

Pharmacological characterisation of a tool αvβ1 integrin small molecule RGD-mimetic inhibitor.

Eur J Pharmacol 2019 Jan 30;842:239-247. Epub 2018 Oct 30.

Fibrosis Discovery Performance Unit, Respiratory TAU, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, UK. Electronic address:

Compound 8 is a selective αvβ1 small molecule inhibitor that has been used in pre-clinical studies to identify and characterise the αvβ1 integrin as a potential target in fibrotic disease. In this study we further investigated the selectivity and pharmacokinetics of compound 8 to determine a link between the levels of αvβ1 engagement required to achieve in vivo pharmacodynamic efficacy. The selectivity of compound 8 for the arginyl-glycinyl-aspartic acid and β1 integrins was measured using purified integrin protein preparations in radioligand binding studies with both labelled ([H]compound 8) and unlabelled versions. The pharmacokinetic profile of compound 8 was completed in in vitro blood protein binding assays and in in vivo studies using male C57BL/6 mouse following i.v. dosing. The high selectivity of compound 8 for αvβ1 over the other αv integrins was confirmed, however a reduced selectivity was demonstrated for the β1 integrin family, with high affinity observed for α4β1 (comparable to αvβ1), moderate affinity for α2β1, α3β1 and α8β1, and low affinity for α5β1 and α9β1. Compound 8 was shown to be cleared quickly from the blood with a short half-life of 0.5 h. In conclusion, the data in this study suggest that compound 8 has the potential to engage a number of integrins in vivo beyond αvβ1, that raises a degree of uncertainty regarding its mechanism of action in models of fibrotic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2018.10.045DOI Listing
January 2019

Discovery of ( S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αβ Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis.

J Med Chem 2018 09 14;61(18):8417-8443. Epub 2018 Sep 14.

Department of Pure & Applied Chemistry , University of Strathclyde , 295 Cathedral Street , Glasgow G1 1XL , Scotland, U.K.

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αβ, αβ, αβ, αβ, and αβ integrins. Numerous analogs with high affinity and selectivity for the αβ integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αβ integrin in a radioligand binding assay (p K = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b00959DOI Listing
September 2018

Safety, tolerability and pharmacokinetics of GSK3008348, a novel integrin αvβ6 inhibitor, in healthy participants.

Eur J Clin Pharmacol 2018 Jun 12;74(6):701-709. Epub 2018 Mar 12.

Respiratory Therapy Area, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK.

Purpose: Inhaled drug delivery is an attractive route by which to deliver drugs to lungs of patients with idiopathic pulmonary fibrosis (IPF). GSK3008348 is a potent and selective small molecule being developed as the first inhaled inhibitor of the αvβ6 integrin for the treatment of IPF. The phase 1 first-time-in-human clinical trial (NCT02612051) presented here was designed to investigate the safety, tolerability and pharmacokinetic (PK) profile of single doses of GSK3008348 in healthy participants.

Methods: Single ascending doses of GSK3008348 were administered to three cohorts of eight healthy participants in a randomised, double-blind, placebo-controlled, 4-period crossover design. Safety, tolerability and PK were assessed after single doses of 1-3000 mcg given by nebulisation.

Results: A total of 29 participants were enrolled and received at least one dose of study treatment. There were no serious adverse events (AE) reported in any participant. No trends or clinically important differences were noted in the incidence or intensity of AEs or other safety assessments. Maximum plasma concentrations of GSK3008348 were generally attained within approximately 30 min after start of nebulisation, with geometric mean terminal elimination half-lives ranging from 7.95 to 10.2 h. Exposures, as measured by area under the plasma concentration-time curve (AUC), were dose proportional across all doses where estimates were possible (100-3000 mcg). Dose normalised geometric mean C increased with dose up to 3000 mcg. This supra proportionality was relatively modest, with a less than 3-fold increase over the range from 30 to 3000 mcg. The reason(s) for this observation are currently not known but may be due to slower absorption at the lowest doses. All exposures were within the exposure margins set by the non-clinical toxicity studies and so this is not expected to have any impact on safety.

Conclusions: In summary, GSK3008348 was well tolerated at single doses up to 3000 mcg in healthy participants, and its PK profile was dose proportional at potentially clinically relevant doses (300-3000 mcg). These findings support further development of GSK3008348 as a novel inhaled treatment option for IPF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00228-018-2435-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942357PMC
June 2018

A Microdose PET Study of the Safety, Immunogenicity, Biodistribution, and Radiation Dosimetry of F-FB-A20FMDV2 for Imaging the Integrin αβ.

J Nucl Med Technol 2018 Jun 2;46(2):136-143. Epub 2018 Feb 2.

Fibrosis Discovery Performance Unit, GlaxoSmithKline R&D, Stevenage, United Kingdom; and

The αβ integrin is involved in the pathogenesis of cancer and fibrosis. A radiolabeled 20-amino-acid αβ-binding peptide, derived from the foot and mouth virus (NAVPNLRGDLQVLAQKVART [A20FMDV2]), has been developed to image αβ levels preclinically. This study was designed to translate these findings into a clinical PET imaging protocol to measure the expression of αβ in humans. Preclinical toxicology was undertaken, and a direct immunoassay was developed for 4-fluorobenzamide (FB)-A20FMDV2. Four healthy human subjects (2 male and 2 female) received a single microdose of F-FB-A20FMDV2 followed by a multibed PET scan of the whole body over more than 3 h. There were no findings in the preclinical toxicology assessments, and no anti-A20FMDV2 antibodies were detected before or after dosing with the PET ligand. The mean and SD of the administered mass of F-FB-A20FMDV2 was 8.7 ± 4.4 μg (range, 2.7-13.0 μg). The mean administered activity was 124 ± 20 MBq (range, 98-145 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the subjects. No significant changes in vital signs, laboratory study results, or electrocardiography results were observed. Uptake of radioactivity was observed in the thyroid, salivary glands, liver, stomach wall, spleen, kidneys, ureters, and bladder. Time-activity curves indicated that the highest activity was in the bladder content, followed by the kidneys, small intestine, stomach, liver, spleen, thyroid, and gallbladder. The largest component of the residence times was the voided urine, followed by muscle, bladder, and liver. Using the mean residence time over all subjects as input to OLINDA/EXM, the effective dose was determined to be 0.0217 mSv/MBq; using residence times from single subjects gave an SD of 0.0020 mSv/MBq from the mean. The critical organ was the urinary bladder, with an absorbed dose of 0.18 mGy/MBq. F-FB-A20FMDV2 successfully passed toxicology criteria, showed no adverse effects in this first-in-humans study, and has an effective dose that enables multiple scans in a single subject.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnmt.117.203547DOI Listing
June 2018

Identification of selective 8-(piperidin-4-yloxy)quinoline sulfone and sulfonamide histamine H receptor antagonists for use in allergic rhinitis.

Bioorg Med Chem Lett 2017 11 9;27(21):4914-4919. Epub 2017 Sep 9.

Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A series of potent, selective and long-acting quinoline-based sulfonamide human H histamine receptor antagonists, designed for once-daily intranasal administration for the treatment of rhinitis were developed. Sulfonamide 33b had a slightly lower affinity for the H receptor than azelastine, had low oral bioavailability in the rat and dog, and was turned over to five major metabolites. Furthermore, 33b had longer duration of action than azelastine in guinea pigs, lower rat brain-penetration, and did not cause time dependent inhibition of CYP2D6 or CYP3A4. The clinical dose in humans is expected to be low (approximately 0.5mg per day) based on the clinical dose used for azelastine and a comparison of efficacy data from animal models for 33b and azelastine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2017.09.020DOI Listing
November 2017

An αv-RGD Integrin Inhibitor Toolbox: Drug Discovery Insight, Challenges and Opportunities.

Angew Chem Int Ed Engl 2018 03 21;57(13):3298-3321. Epub 2018 Feb 21.

Fibrosis DPU, Respiratory Therapeutic Area, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK.

There is a requirement for efficacious and safe medicines to treat diseases with high unmet need. The resurgence in αv-RGD integrin inhibitor drug discovery is poised to contribute to this requirement. However, drug discovery in the αv integrin space is notoriously difficult due to the receptors being structurally very similar as well as the polar zwitterionic nature of the pharmacophore. This Review aims to guide drug discovery research in this field through an αv inhibitor toolbox, consisting of small molecules and antibodies. Small-molecule αv tool compounds with extended profiles in αvβ1, 3, 5, 6 and 8 cell adhesion assays, with key physicochemical properties, have been collated to assist in the selection of the right tool for the right experiment. This should also facilitate an understanding of partial selectivity profiles of compounds generated in different assays across research institutions. Prospects for further αv integrin research and the critical importance of target validation are discussed, where increased knowledge of the selectivity for individual RGD αv integrins is key. Insights into the design of small-molecule RGD chemotypes for topical or oral administration are provided and clinical findings on advanced molecules are examined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201707948DOI Listing
March 2018

Design of Phthalazinone Amide Histamine H Receptor Antagonists for Use in Rhinitis.

ACS Med Chem Lett 2017 May 21;8(5):577-581. Epub 2017 Apr 21.

Medicinal Chemistry, Respiratory Biology, R&D Platform Technology and Science, and Drug Metabolism and Pharmacokinetcs, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

The synthesis of potent amide-containing phthalazinone H histamine receptor antagonists is described. Three analogues , , and were equipotent with azelastine and were longer-acting in vitro. Amide had low oral bioavailability, low brain-penetration, high metabolic clearance, and long duration of action in vivo, and it was suitable for once-daily dosing intranasally, with a predicted dose for humans of approximately 0.5 mg per day.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.7b00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430406PMC
May 2017

Determining the True Selectivity Profile of αv Integrin Ligands Using Radioligand Binding: Applying an Old Solution to a New Problem.

SLAS Discov 2017 Sep 17;22(8):962-973. Epub 2017 Apr 17.

2 Fibrosis Discovery Performance Unit, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK.

The arginyl-glycinyl-aspartic acid (RGD) integrin subfamily contains five members that partner with the αv subunit: αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8. Within the αv integrins, the epithelially restricted αvβ6 has been identified as playing a key role in the activation of transforming growth factor β that is hypothesized to be pivotal in the development of idiopathic pulmonary fibrosis (IPF). As part of a drug discovery program to identify a selective αvβ6 RGD mimetic for IPF, cell adhesion and radioligand binding assays were investigated to screen compounds to determine affinity and αv integrin selectivity. In this study, a pan-αv radioligand was characterized against all the αv integrins and used to determine accurate selectivity profiles for literature and novel RGD ligands, as well as enable an early readout on αvβ6 dissociation kinetics. It has been shown that while cell adhesion offers a high throughput and reliable format for ranking compounds, there are downsides to this format when comparing selectivity across αv integrins. By accurately defining the relationship between these assay formats, a medicinal chemistry effort has identified novel, high-affinity, and selective αvβ6 RGD mimetics with slow dissociation kinetics, with the potential to be developed into clinical candidates for IPF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2472555217703908DOI Listing
September 2017

The discovery of quinoline based single-ligand human H and H receptor antagonists.

Bioorg Med Chem Lett 2016 12 10;26(24):5855-5859. Epub 2016 Nov 10.

Respiratory Biology, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A novel series of potent quinoline-based human H and H bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H potency (pA 8.8 vs 9.7 for the clinical goldstandard azelastine), and H potency (pK 9.1vs 6.8 for azelastine), better selectivity over α, α and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2016.11.022DOI Listing
December 2016

Characterisation of a novel, high affinity and selective αvβ6 integrin RGD-mimetic radioligand.

Biochem Pharmacol 2016 10 5;117:88-96. Epub 2016 Aug 5.

Fibrosis and Lung Injury Discovery Performance Unit, Respiratory TAU, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, UK. Electronic address:

The alpha-v beta-6 (αvβ6) integrin has been identified as playing a key role in the activation of transforming growth factor-β (TGFβ) that is hypothesised to be pivotal in the development of cancer and fibrotic diseases. Therefore, the αvβ6 integrin is an attractive therapeutic target for these debilitating diseases and a drug discovery programme to identify small molecule αvβ6 selective arginyl-glycinyl-aspartic acid (RGD)-mimetics was initiated within GlaxoSmithKline. The primary aim of this study was to pharmacologically characterise the binding to αvβ6 of a novel clinical candidate, compound 1, using a radiolabelled form. Radioligand binding studies were completed with [(3)H]compound 1 against the human and mouse soluble protein forms of αvβ6 to determine accurate affinity estimates and binding kinetics. The selectivity of compound 1 for the RGD integrin family was also determined using saturation binding studies (αvβ1, αvβ3, αvβ5, αvβ8, α5β1 and α8β1 integrins) and fibrinogen-induced platelet aggregation (αIIbβ3 integrin). In addition, the relationship between divalent metal cation type and concentration and αvβ6 RGD site binding was also investigated. Compound 1 has been demonstrated to bind with extremely high affinity and selectivity for the αvβ6 integrin and has the potential as a clinical tool and therapeutic for investigating the role of αvβ6 in a range of disease states both pre-clinically and clinically. In addition, this is the first study that has successfully applied radioligand binding to the RGD integrin field to accurately determine the affinity and selectivity profile of a small molecule RGD-mimetic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2016.08.003DOI Listing
October 2016

2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis.

Eur J Med Chem 2016 Jun 27;115:14-25. Epub 2016 Feb 27.

Department of Respiratory Biology, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.

A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [(125)I]-TARC binding assay with a pKi of 8.8, and the [(35)S]-GTPγS functional assay with a pIC50 of 8.1, and high activity in the human whole blood actin polymerisation assay (pA2 = 6.7). The most potent antagonists were also investigated for their ability to induce endocytosis of CCR4 and were found to internalise about 60% of the cell surface receptors, a property which is not commonly shared by small molecule antagonists of chemokine receptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2016.02.058DOI Listing
June 2016

Pharmacological Characterization of the αvβ6 Integrin Binding and Internalization Kinetics of the Foot-and-Mouth Disease Virus Derived Peptide A20FMDV2.

Pharmacology 2016 7;97(3-4):114-25. Epub 2016 Jan 7.

Fibrosis and Lung Injury Discovery Performance Unit, Respiratory TAU, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, UK.

A20FMDV2 is a peptide derived from the foot-and-mouth disease virus with a high affinity and selectivity for the alpha-v beta-6 (αvβ6) arginyl-glycinyl-aspartic acid (RGD)-binding integrin. It has been shown to be an informative tool ligand in pre-clinical imaging studies for selective labelling of the αvβ6 integrin in a number of disease models. In a radioligand binding assay using a radiolabelled form of the peptide ([3H]A20FMDV2), its high affinity (K(D): 0.22 nmol/l) and selectivity (at least 85-fold) for αvβ6 over the other members of the RGD integrin family was confirmed. [3H]A20FMDV2 αvβ6 binding could be fully reversed only in the presence of EDTA, whereas a partial reversal was observed in the presence of excess concentrations of an RGD-mimetic small molecule (SC-68448) or unlabelled A20FMDV2. Using flow cytometry on bronchial epithelial cells, the ligand-induced internalization of αvβ6 by A20FMDV2 and latency-associated peptide-1 was shown to be fast (t(1/2): 1.5 and 3.1 min, respectively), concentration-dependent (EC50: values 1.1 and 3.6 nmol/l, respectively) and was followed by a moderately slow return of integrin to the surface. The results of the radioligand binding studies suggest that the binding of A20FMDV2 to the RGD-binding site on αvβ6 is required to maintain its engagement with the hypothesised A20FMDV2 synergy site on the integrin. In addition, there is evidence from flow cytometric studies that the RGD-ligand engagement of αvβ6 post-internalization plays a role in delaying recycling of the integrin to the cell surface. This mechanism may act as a homeostatic control of membrane αvβ6 following RGD ligand engagement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000443180DOI Listing
December 2016

Antagonism of human CC-chemokine receptor 4 can be achieved through three distinct binding sites on the receptor.

Pharmacol Res Perspect 2013 Dec 30;1(2):e00019. Epub 2013 Dec 30.

Lead Optimisation, Respiratory CEDD, GlaxoSmithKline Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK.

Chemokine receptor antagonists appear to access two distinct binding sites on different members of this receptor family. One class of CCR4 antagonists has been suggested to bind to a site accessible from the cytoplasm while a second class did not bind to this site. In this report, we demonstrate that antagonists representing a variety of structural classes bind to two distinct allosteric sites on CCR4. The effects of pairs of low-molecular weight and/or chemokine CCR4 antagonists were evaluated on CCL17- and CCL22-induced responses of human CCR4(+) T cells. This provided an initial grouping of the antagonists into sets which appeared to bind to distinct binding sites. Binding studies were then performed with radioligands from each set to confirm these groupings. Some novel receptor theory was developed to allow the interpretation of the effects of the antagonist combinations. The theory indicates that, generally, the concentration-ratio of a pair of competing allosteric modulators is maximally the sum of their individual effects while that of two modulators acting at different sites is likely to be greater than their sum. The low-molecular weight antagonists could be grouped into two sets on the basis of the functional and binding experiments. The antagonistic chemokines formed a third set whose behaviour was consistent with that of simple competitive antagonists. These studies indicate that there are two allosteric regulatory sites on CCR4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/prp2.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186434PMC
December 2013

Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases.

J Pharmacol Exp Ther 2013 May 22;345(2):260-70. Epub 2013 Feb 22.

GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, USA.

Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs) increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719 (4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane; umeclidinium). The affinity (Ki) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. Dissociation of [(3)H]GSK573719 from the M3 mAChR was slower than that for the M2 mAChR [half-life (t1/2) values: 82 and 9 minutes, respectively]. In Chinese hamster ovary cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated picomolar potency (-log pA2 = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug washout. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol, and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 minutes (versus 413 minutes for tiotropium bromide). In mice, the ED50 value was 0.02 μg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose dependently blocked Ach-induced bronchoconstriction with long duration of action, and was comparable to tiotropium; 2.5 μg elicited 50% bronchoprotection for >24 hours. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into a 24-hour duration of bronchodilation in vivo, which suggested umeclidinium will be a once-daily inhaled treatment of pulmonary diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.112.202051DOI Listing
May 2013

Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.

J Med Chem 2013 Mar 27;56(5):1946-60. Epub 2013 Feb 27.

Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm301572hDOI Listing
March 2013

In vitro pharmacological characterization of vilanterol, a novel long-acting β2-adrenoceptor agonist with 24-hour duration of action.

J Pharmacol Exp Ther 2013 Jan 6;344(1):218-30. Epub 2012 Nov 6.

Respiratory TAU, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.

Vilanterol trifenatate (vilanterol) is a novel, long-acting β(2)-adrenoceptor (β(2)-AR) agonist with 24 h activity. In this study, we describe the preclinical pharmacological profile of vilanterol using radioligand binding and cAMP studies in recombinant assays as well as human and guinea pig tissue systems to characterize β(2)-AR binding and functional properties. Vilanterol displayed a subnanomolar affinity for the β(2)-AR that was comparable with that of salmeterol but higher than olodaterol, formoterol, and indacaterol. In cAMP functional activity studies, vilanterol demonstrated similar selectivity as salmeterol for β(2)- over β(1)-AR and β(3)-AR, but a significantly improved selectivity profile than formoterol and indacaterol. Vilanterol also showed a level of intrinsic efficacy that was comparable to indacaterol but significantly greater than that of salmeterol. In cellular cAMP production and tissue-based studies measuring persistence and reassertion, vilanterol had a persistence of action comparable with indacaterol and longer than formoterol. In addition, vilanterol demonstrated reassertion activity in both cell and tissue systems that was comparable with salmeterol and indacaterol but longer than formoterol. In human airways, vilanterol was shown to have a faster onset and longer duration of action than salmeterol, exhibiting a significant level of bronchodilation 22 h after treatment. From these investigations, the data for vilanterol are consistent, showing that it is a novel, potent, and selective β(2)-AR receptor agonist with a long duration of action. This pharmacological profile combined with clinical data is consistent with once a day dosing of vilanterol in the treatment of both asthma and chronic obstructive pulmonary disease (COPD).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.112.198481DOI Listing
January 2013

Synthesis and pharmacological investigation of azaphthalazinone human histamine H(1) receptor antagonists.

Bioorg Med Chem 2012 Oct 31;20(20):6097-108. Epub 2012 Aug 31.

Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

5-Aza, 6-aza, 7-aza and 8-aza-phthalazinone, and 5,8-diazaphthalazinone templates were synthesised by stereoselective routes starting from the appropriate pyridine/pyrazine dicarboxylic acids by activation with CDI, reaction with 4-chlorophenyl acetate ester enolate to give a β-ketoester, which was hydrolysed, and decarboxylated. The resulting ketone was condensed with hydrazine to form the azaphthalazinone core. The azaphthalazinone cores were alkylated with N-Boc-D-prolinol at N-2 by Mitsunobu reaction, de-protected, and then alkylated at the pyrrolidine nitrogen to provide the target H(1) receptor antagonists. All four mono-azaphthalazinone series had higher affinity (pK(i)) for the human H(1) receptor than azelastine, but were not as potent as the parent non-aza phthalazinone. The 5,8-diazaphthalazinone was equipotent with azelastine. The least potent series were the 7-azaphthalazinones, whereas the 5-azaphthalazinones were the most lipophilic. The more hydrophilic series were the 8-aza series. Replacement of the N-methyl substituent on the pyrrolidine with the n-butyl group caused an increase in potency (pA(2)) and a corresponding increase in lipophilicity. Introduction of a β-ether oxygen in the n-butyl analogues (2-methoxyethyl group) decreased the H(1) pA(2) slightly, and increased the selectivity against hERG. The duration of action in vitro was longer in the 6-azaphthalazinone series. The more potent and selective 6-azaphthalazinone core was used to append an H(3) receptor antagonist fragment, and to convert the series into the long acting single-ligand, dual H(1) H(3) receptor antagonist 44. The pharmacological profile of 44 was very similar to our intranasal clinical candidate 1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2012.08.032DOI Listing
October 2012

Lead optimisation of the N1 substituent of a novel series of indazole arylsulfonamides as CCR4 antagonists and identification of a candidate for clinical investigation.

Bioorg Med Chem Lett 2012 Apr 7;22(8):2730-3. Epub 2012 Mar 7.

Department of Medicinal Chemistry, Respiratory CEDD, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, United Kingdom.

Synthesis and preliminary SAR of the N1 substituent of a novel series of indazole sulfonamide chemokine receptor 4 (CCR4) antagonist is reported. Compound 7r was identified for further development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2012.02.104DOI Listing
April 2012

In vitro characterisation of the duration of action of the histamine-1 receptor antagonist azelastine.

Eur J Pharmacol 2011 Nov 21;670(2-3):586-92. Epub 2011 Sep 21.

Respiratory CEDD Biology, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, UK.

Azelastine is a selective antagonist at the human histamine-1 receptor and is used clinically in the treatment of allergic rhinitis. In this study we have investigated its duration of action in vitro in an effort to characterise the receptor and tissue components involved. Chinese hamster ovary cell membrane fragments were used to determine the kinetics of azelastine at the H₁ receptor in a radioligand binding assay. Further duration of action studies were completed in tissue preparations using guinea-pig trachea and human bronchus. In radioligand binding studies, azelastine reached steady state at the H₁ receptor after approximately 41 min and exhibited a significantly slower dissociation rate constant from the receptor than the first generation antihistamine, diphenhydramine. In washout studies completed in guinea-pig and human airway in vitro tissue preparations, azelastine continued to antagonise the effects of histamine at the H₁ receptor for at least 18 h post-washout of the antagonist. This outcome was reversed following removal of the epithelium from guinea-pig isolated tracheal strips. These studies indicate there is a tissue component contributing to azelastine's duration of action, in addition to its direct H₁ receptor binding, with evidence suggesting a role for the epithelial layer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2011.09.017DOI Listing
November 2011

The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis.

J Med Chem 2011 Apr 7;54(7):2183-95. Epub 2011 Mar 7.

Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.

A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm1013874DOI Listing
April 2011

Evaluation of Patient Navigation in a Community Radiation Oncology Center Involved in Disparities Studies: A Time-to-Completion-of-Treatment Study.

J Oncol Pract 2008 ;4(5):220-224

University of Pittsburgh Medical Center/Jameson Cancer Center, Jameson Memorial Hospital, New Castle; and Radiation Oncology Community Outreach Group, McKeesport, PA.

PURPOSE: To evaluate whether data on length of time from patient referral to treatment completion, collected routinely as part of a quality improvement program, can be used to measure the effectiveness of a patient navigator program. PATIENTS AND METHODS: During a calendar year, 72 disparities patients, 38 of whom received navigator services, and a group of 157 nondisparate, un-navigated patients received external beam radiation therapy at a community center. Data from referral time through completion of treatment, which had been collected routinely under an existing continuous quality improvement program, were compared retrospectively, as well as missed treatments and the percentage of planned treatments completed, for three patient groups. RESULTS: The average number of days from referral to consult and from consult to start of treatment were lower for the navigated disparate group (6.66 and 14.56 days, respectively) than un-navigated groups (disparate: 7.37 and 15.97 days; non-disparate: 8.97 and 16.24 days, respectively). The percentage of patients completing treatment was lower for the navigated group (85%) than the un-navigated groups (95% and 97%), despite equivalent treatment percentage completion rates for all groups (97.0% to 98.8%). The navigated group missed more treatment days (1.86 days/patient) than the un-navigated disparate group (0.47 days/patient) or the non-disparate group (0.83 days/patient.) CONCLUSION: Some statistically insignificant differences were noted in favor of patient navigation (PN) but the significance is unclear because of the large data spread and the small numbers of patients. Given that the study was retrospective, it is also unclear whether these differences were influenced by the patient navigator. Repeat studies using the same data elements will provide a better platform for assessing whether such data can provide a measure of the effectiveness of PN in the radiation oncology setting. Given that the patients were not observed routinely by the navigator after the start of treatment unless a particular barrier was identified, there is an opportunity to assess whether interventions by the navigator could improve treatment completion rates and reduce the number of missed treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JOP.0852001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630161PMC
January 2008