Publications by authors named "David Sandham"

22 Publications

  • Page 1 of 1

The pharmacology of the prostaglandin D receptor 2 (DP) receptor antagonist, fevipiprant.

Pulm Pharmacol Ther 2021 Apr 4;68:102030. Epub 2021 Apr 4.

Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover, NJ, 07936, USA.

Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the prostaglandin D (DP) receptor. The DP receptor is a mediator of inflammation expressed on the membrane of key inflammatory cells, including eosinophils, Th2 cells, type 2 innate lymphoid cells, CD8 cytotoxic T cells, basophils and monocytes, as well as airway smooth muscle and epithelial cells. The DP receptor pathway regulates the allergic and non-allergic asthma inflammatory cascade and is activated by the binding of prostaglandin D. Fevipiprant is metabolised by several uridine 5'-diphospho glucuronosyltransferase enzymes to an inactive acyl-glucuronide (AG) metabolite, the only major human metabolite. Both fevipiprant and its AG metabolite are eliminated by urinary excretion; fevipiprant is also possibly cleared by biliary excretion. These parallel elimination pathways suggested a low risk of major drug-drug interactions (DDI), pharmacogenetic or ethnic variability for fevipiprant, which was supported by DDI and clinical studies of fevipiprant. Phase II clinical trials of fevipiprant showed reduction in sputum eosinophilia, as well as improvement in lung function, symptoms and quality of life in patients with asthma. While fevipiprant reached the most advanced state of development to date of an oral DP receptor antagonist in a worldwide Phase III clinical trial programme, the demonstrated efficacy did not support further clinical development in asthma.
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http://dx.doi.org/10.1016/j.pupt.2021.102030DOI Listing
April 2021

Fevipiprant, a selective prostaglandin D receptor 2 antagonist, inhibits human group 2 innate lymphoid cell aggregation and function.

J Allergy Clin Immunol 2019 06 28;143(6):2329-2333. Epub 2019 Feb 28.

MRC Human Immunology Unit and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.02.015DOI Listing
June 2019

Fevipiprant, a DP receptor antagonist, inhibits eosinophil migration towards mast cells.

Clin Exp Allergy 2019 02 25;49(2):255-257. Epub 2018 Nov 25.

The Hebrew University of Jerusalem, Jerusalem, Israel.

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http://dx.doi.org/10.1111/cea.13304DOI Listing
February 2019

The prostaglandin D receptor 2 pathway in asthma: a key player in airway inflammation.

Respir Res 2018 Sep 29;19(1):189. Epub 2018 Sep 29.

Novartis Pharmaceuticals Corporation, One Health Plaza East Hanover, East Hanover, NJ, 07936-1080, USA.

Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response.Prostaglandin D (PGD) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as T2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD mainly exerts its biological functions via two G-protein-coupled receptors, the PGD receptor 1 (DP) and 2 (DP). The DP receptor is mainly expressed by the key cells involved in type 2 immune responses, including T2 cells, type 2 innate lymphoid cells and eosinophils. The DP receptor pathway is a novel and important therapeutic target for asthma, because increased PGD production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP receptor pathway and the current understanding of its role in asthma.
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http://dx.doi.org/10.1186/s12931-018-0893-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162887PMC
September 2018

Interactions between β2-Adrenoceptor Ligands and Membrane: Atomic-Level Insights from Magic-Angle Spinning NMR.

J Med Chem 2017 08 4;60(16):6867-6879. Epub 2017 Aug 4.

Global Discovery Chemistry, Novartis Institutes for BioMedical Research , Cambridge, Massachusetts 02139, United States.

To understand the relationship between structural properties of the β2-adrenoceptor ligands and their interactions with membranes, we have investigated the location and distribution of five β2 agonists with distinct clinical durations and onsets of action (indacaterol, two indacaterol analogues, salmeterol and formoterol) in monounsaturated model membranes using magic angle spinning NMR to measure these interactions through both H nuclear Overhauser enhancement (NOE) and paramagnetic relaxation enhancement (PRE) techniques. The hydrophilic aromatic groups of all five β2 agonists show maximum distribution in the lipid/water interface, but distinct location and dynamic behavior were observed for the lipophilic aromatic rings. Our study elucidates at atomic level that the hydrophobicity and substitution geometry of lipophilic groups play important roles in compound-lipid interactions.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00205DOI Listing
August 2017

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP Receptor Antagonist for Treatment of Asthma.

ACS Med Chem Lett 2017 May 25;8(5):582-586. Epub 2017 Apr 25.

Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.

Further optimization of an initial DP receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1-pyrrolo[2,3-]pyridin-3-yl)acetic acid (compound , NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430394PMC
May 2017

Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo-Controlled Studies in Healthy Volunteers.

Clin Pharmacol Drug Dev 2016 Jul 28;5(4):306-13. Epub 2016 Mar 28.

Novartis Pharma AG, Basel, Switzerland.

We evaluated the pharmacokinetics (PK), safety, and tolerability of a novel oral CRTh2 antagonist, fevipiprant (QAW039), in healthy subjects. Peak concentrations of fevipiprant in plasma were observed 1-3 hours postdosing. Concentrations declined in a multiexponential manner, followed by an apparent terminal phase (t1/2 , ∼20 hours). Steady state was achieved in 4 days with <2-fold accumulation. Elimination was partly by renal excretion (≤30% of the dose) and glucuronidation. Food had minimal impact on the PK of fevipiprant, and it was well tolerated at single and multiple oral doses up to 500 mg/day. No dose-dependent adverse events were observed, and all the events were mild or moderate in severity. Systemic concentrations were sufficiently high to achieve relevant target occupancy, considering in vitro pharmacology data. In summary, the data support further development as a once-daily oral therapy for allergic diseases.
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http://dx.doi.org/10.1002/cpdd.244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071756PMC
July 2016

Uncoupling the Structure-Activity Relationships of β2 Adrenergic Receptor Ligands from Membrane Binding.

J Med Chem 2016 06 7;59(12):5780-9. Epub 2016 Jun 7.

Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.

Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. In particular, the microscopic ligand concentration within the membrane surface solvation layer may exceed that in bulk solvent, resulting in overestimation of the intrinsic protein-ligand binding contribution to the apparent/measured affinity. Using published binding data for a set of small molecules with the β2 adrenergic receptor, we demonstrate that deconvolution of membrane and protein binding contributions allows for improved structure-activity relationship analysis and structure-based drug design. Molecular dynamics simulations of ligand bound membrane protein complexes were used to validate binding poses, allowing analysis of key interactions and binding site solvation to develop structure-activity relationships of β2 ligand binding. The resulting relationships are consistent with intrinsic binding affinity (corrected for membrane interaction). The successful structure-based design of ligands targeting membrane proteins may require an assessment of membrane affinity to uncouple protein binding from membrane interactions.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00358DOI Listing
June 2016

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy.

Mol Pharmacol 2016 May 25;89(5):593-605. Epub 2016 Feb 25.

Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK (D.A.Sy., S.J.C.)

Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [(3)H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D2(PGD2). The binding kinetics of QAW039 determined directly using [(3)H]-QAW039 revealed mean kinetic on (kon) and off (koff) values for QAW039 of 4.5 × 10(7)M(-1)min(-1)and 0.048 minute(-1), respectively. Importantly, thekoffof QAW039 (half-life = 14.4 minutes) was >7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD2-stimulated [(35)S]-GTPγS activation, and its effects were not fully reversed by increasing concentrations of PGD2after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for >180 minutes. All CRTh2 antagonists tested inhibited PGD2-stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD2-induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD2concentrations, which may be clinically relevant.
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http://dx.doi.org/10.1124/mol.115.101832DOI Listing
May 2016

Synthetic approaches to site selective deuterium incorporation in a novel CRTh2 receptor antagonist clinical candidate.

J Labelled Comp Radiopharm 2014 Mar 23;57(3):175-7. Epub 2014 Jan 23.

Global Discovery Chemistry, Novartis Institutes of Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, RH12 5AB, UK.

Selection of acidic or basic reaction conditions, combined with appropriate temperatures, allowed for site selective direct incorporation of deuterium at multiple positions in the 7-azaindole-3-acetic acid CRTh2 receptor antagonist clinical candidate NVP-QAV680.
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http://dx.doi.org/10.1002/jlcr.3174DOI Listing
March 2014

Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases.

Bioorg Med Chem 2013 Nov 22;21(21):6582-91. Epub 2013 Aug 22.

Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom. Electronic address:

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.
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http://dx.doi.org/10.1016/j.bmc.2013.08.025DOI Listing
November 2013

An investigation into the structure-activity relationships associated with the systematic modification of the β(2)-adrenoceptor agonist indacaterol.

Bioorg Med Chem Lett 2012 Oct 4;22(19):6280-5. Epub 2012 Aug 4.

Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom.

The synthesis of a series of indacaterol analogues in which each of the three structural regions of indacaterol are modified in a systematic manner is described. Evaluation of the affinity of these analogues for the β(2)-adrenoceptor identified the 3,4-dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacaterol. An α-methyl aminoindane analogue was discovered to be 25-fold more potent than indacaterol, and functional studies revealed an atypical β(2)-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating 'super agonist'.
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http://dx.doi.org/10.1016/j.bmcl.2012.07.096DOI Listing
October 2012

Synthesis of useful fragments in drug discovery: 2-Amino-5-tert-butylpyridine and its oxidised analogues.

Bioorg Med Chem Lett 2011 Jul 25;21(14):4281-3. Epub 2011 May 25.

Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.

A novel and robust synthesis of the fragment, 2-amino-5-tert-butylpyridine, has been described, which has been shown to have improved physicochemical properties over 4-tert-butylaniline, when considering drug-like properties. The synthesis also yields fragments containing more highly oxidised precursors to the tert-butyl group as intermediates. These fragments can be incorporated into final target molecules, yielding pharmaceutical compounds and their putative CYP-mediated oxidative metabolites, which can aid in elucidation of metabolic clearance processes.
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http://dx.doi.org/10.1016/j.bmcl.2011.05.066DOI Listing
July 2011

7-Azaindole-3-acetic acid derivatives: potent and selective CRTh2 receptor antagonists.

Bioorg Med Chem Lett 2009 Aug 14;19(16):4794-8. Epub 2009 Jun 14.

Global Discovery Chemistry, Novartis Institutes of Biomedical Research, Horsham Research Centre, Horsham, West Sussex RH12 5AB, United Kingdom.

High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat.
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http://dx.doi.org/10.1016/j.bmcl.2009.06.042DOI Listing
August 2009

2-Cycloalkyl phenoxyacetic acid CRTh2 receptor antagonists.

Bioorg Med Chem Lett 2007 Aug 13;17(15):4347-50. Epub 2007 May 13.

Global Discovery Chemistry, Novartis Institutes of Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK.

High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.
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http://dx.doi.org/10.1016/j.bmcl.2007.05.019DOI Listing
August 2007

A microwave enhanced cross-metathesis approach to peptidomimetics.

Org Biomol Chem 2007 Apr 5;5(7):1025-7. Epub 2007 Feb 5.

University College London, Department of Chemistry, Christopher Ingold Laboratories, 20 Gordon Street, London, UK.

Functionalization of amino acid C- and N-termini with appropriate olefinic moieties allows for the generation of a peptidomimetic via a stereoselective cross-metathesis.
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http://dx.doi.org/10.1039/b700804jDOI Listing
April 2007

Potent and selective xanthine-based inhibitors of phosphodiesterase 5.

Bioorg Med Chem Lett 2007 Apr 10;17(8):2376-9. Epub 2006 Nov 10.

Novartis Institutes of Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK.

Inhibitors of PDE5 are useful therapeutic agents for treatment of erectile dysfunction. A series of novel xanthine derivatives has been identified as potent inhibitors of PDE5, with good levels of selectivity against other PDE isoforms, including PDE6. Studies in the dog indicate excellent oral bioavailability for compound 21.
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http://dx.doi.org/10.1016/j.bmcl.2006.11.019DOI Listing
April 2007

Synthesis and biological properties of novel glucocorticoid androstene C-17 furoate esters.

Bioorg Med Chem 2004 Oct;12(19):5213-24

Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom.

A series of novel corticosteroid derivatives featuring C-17 furoate ester functionality have been synthesised. Profiling in vitro and in vivo has resulted in the identification of a compound with a longer duration of action and a lower oral side effect profile in rodents compared to budesonide.
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http://dx.doi.org/10.1016/j.bmc.2004.06.027DOI Listing
October 2004

Studies on high-temperature amination reactions of aromatic chlorides using discrete palladium-N-heterocyclic carbene (NHC) complexes and in situ palladium/imidazolium salt protocols.

Mol Divers 2003 ;7(2-4):115-23

The Chemistry Laboratory, School of Chemistry, Physics and Environmental Sciences, University of Sussex, Falmer Brighton, UK.

The palladium catalysed coupling of aryl chlorides and amines can be readily achieved with short reaction times when carried out at high temperatures under thermal or microwave conditions. These coupling protocols are successful using two co-ordinate palladium-N-heterocyclic carbene complexes, or imidazolium salt protocols.
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http://dx.doi.org/10.1023/b:modi.0000006863.14423.daDOI Listing
September 2004

Recent advances in corticosteroids for the treatment of asthma.

Curr Opin Investig Drugs 2002 Aug;3(8):1149-56

Novartis Horsham Research Centre, West Sussex, UK.

The currently available therapy for asthma is highly effective and is able to control the disease in the majority of patients. There are two types of treatments for asthma: rapid relief of symptoms, used as needed and long-term control, used on a regular basis. Rapid relief is provided by short-acting beta2-agonists and anticholinergics. The control of asthma is achieved by treatment with inhaled corticosteroids (ICS), theophylline, long acting beta2-agonists and antileukotrienes. Beta2-agonists and corticosteroids dominate asthma therapy, with over 65% of the market share. Corticosteroids are the most effective drugs available to clinicians for the control of inflammation in patients with asthma. ICS have revolutionized the treatment of asthma and are now the first-line treatment for chronic asthma in all ages.
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August 2002

8-Aryl xanthines potent inhibitors of phosphodiesterase 5.

Bioorg Med Chem Lett 2002 Sep;12(18):2587-90

Novartis Horsham Research Centre, Wimblehurst Road, West Sussex RH12 5AB, Horsham, UK.

In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms.
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http://dx.doi.org/10.1016/s0960-894x(02)00480-8DOI Listing
September 2002