Publications by authors named "Anne E Cooper"

7 Publications

  • Page 1 of 1

Understanding Exposure-Receptor Occupancy Relationships for Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators across a Range of Preclinical and Clinical Studies.

J Pharmacol Exp Ther 2021 04 4;377(1):157-168. Epub 2021 Feb 4.

Sosei Heptares, Cambridge, CB21 6DG, United Kingdom.

The metabotropic glutamate receptor 5 (mGlu) is a recognized central nervous system therapeutic target for which several negative allosteric modulator (NAM) drug candidates have or are continuing to be investigated for various disease indications in clinical development. Direct measurement of target receptor occupancy (RO) is extremely useful to help design and interpret efficacy and safety in nonclinical and clinical studies. In the mGlu field, this has been successfully achieved by monitoring displacement of radiolabeled ligands, specifically binding to the mGlu receptor, in the presence of an mGlu NAM using in vivo and ex vivo binding in rodents and positron emission tomography imaging in cynomolgus monkeys and humans. The aim of this study was to measure the RO of the mGlu NAM HTL0014242 in rodents and cynomolgus monkeys and to compare its plasma and brain exposure-RO relationships with those of clinically tested mGlu NAMs dipraglurant, mavoglurant, and basimglurant. Potential sources of variability that may contribute to these relationships were explored. Distinct plasma exposure-response relationships were found for each mGlu NAM, with >100-fold difference in plasma exposure for a given level of RO. However, a unified exposure-response relationship was observed when both unbound brain concentration and mGlu affinity were considered. This relationship showed <10-fold overall difference, was fitted with a Hill slope that was not significantly different from 1, and appeared consistent with a simple E model. This is the first time this type of comparison has been conducted, demonstrating a unified brain exposure-RO relationship across several species and mGlu NAMs with diverse properties. SIGNIFICANCE STATEMENT: Despite the long history of mGlu as a therapeutic target and progression of multiple compounds to the clinic, no formal comparison of exposure-receptor occupancy relationships has been conducted. The data from this study indicate for the first time that a consistent, unified relationship can be observed between exposure and mGlu receptor occupancy when unbound brain concentration and receptor affinity are taken into account across a range of species for a diverse set of mGlu negative allosteric modulators, including a new drug candidate, HTL0014242.
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http://dx.doi.org/10.1124/jpet.120.000371DOI Listing
April 2021

Optimisation of DMPK by the inhaled route: challenges and approaches.

Curr Drug Metab 2012 May;13(4):457-73

Discovery DMPK, Astra- Zeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, UK.

The renewed interest in inhalation delivery over recent years has led to an expansion in the understanding of lung pharmacokinetics. Historically optimisation of inhaled drugs focused largely on development of material properties, consistent with achieving a good lung deposition, alongside demonstrating appropriate in vivo efficacy with little understanding of the relationship to pharmacokinetics in the lung. Recent efforts have led to an increased understanding of lung concentrations and how to maximise exposure in order to achieve the desired pharmacological response at a dose consistent with development of an inhaled product. Although there is a prerequisite for excellent potency in inhalation delivery, it is essential that this be combined with pharmacokinetic properties that allow sufficient free concentration at the effect site in lung to exert the pharmacological response for an appropriate dosing interval. Increases in basicity, polarity and/or decreases in aqueous solubility can extend pharmacokinetic duration and assist in finding the right balance between lung and systemic exposure. Current evidence suggests there are similarities in lung retention in rat and dog and that animal lung concentration data can enable pharmacokinetic-pharmacodynamic relationships to be derived thus providing more confidence in the requirements for man. Although inhaled delivery is challenging from a pharmacokinetic point of view, direct evaluation of exposure in the target organ has enabled further understanding of the drivers for drug disposition and highlighted the need for further development of predictive lung pharmacokinetic tools in the future.
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http://dx.doi.org/10.2174/138920012800166571DOI Listing
May 2012

Modulators of the human CCR5 receptor. Part 3: SAR of substituted 1-[3-(4-methanesulfonylphenyl)-3-phenylpropyl]-piperidinyl phenylacetamides.

Bioorg Med Chem Lett 2006 Jul 2;16(13):3533-6. Epub 2006 May 2.

Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.

SAR and PK studies led to the identification of N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[4-methanesulfonylphenyl] propyl}piperidin-4-yl)-N-ethyl-2-[4-methanesulfonylphenyl]acetamide as a highly potent and selective ligand for the human CCR5 chemokine receptor with good oral pharmacokinetic properties.
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http://dx.doi.org/10.1016/j.bmcl.2006.03.089DOI Listing
July 2006

Modulators of the human CCR5 receptor. Part 2: SAR of substituted 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides.

Bioorg Med Chem Lett 2005 Nov;15(22):5012-5

Respiratory & Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.

SAR and DMPK studies led to the identification of substituted N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides as potent and orally bioavailable ligands for the human CCR5 chemokine receptor.
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http://dx.doi.org/10.1016/j.bmcl.2005.08.014DOI Listing
November 2005

P-glycoprotein potentiates CYP3A4-mediated drug disappearance during Caco-2 intestinal secretory detoxification.

J Drug Target 2004 ;12(7):405-13

Institute for Cell and Molecular Biosciences, University of Newcastle Medical School, Newcastle upon Tyne NE2 4HH, UK.

Human intestinal Caco-2 cell monolayers grown in the presence of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) were used to test the hypothesis that drugs which interact with the apical efflux pump P-glycoprotein (Pgp) may enhance CYP3A4-mediated disappearance of substrates. 6beta-hydroxytestosterone production, a marker of CYP3A4 activity, was approximately 3- and 7-fold greater in 1,25(OH)2D3-treated cells compared to untreated cells when incubated with 50 and 500 microM testosterone, respectively, and was unaffected by the addition of digoxin to reduce Pgp activity. In the presence of digoxin, secretory transport of vinblastine and erythromycin, substrates for both Pgp and cytochrome P450 3A4 (CYP3A4), was significantly reduced, whereas absorptive transport was unaffected. In contrast, no directional transport of testosterone, a substrate for CYP3A4 only, was observed, either in the presence or absence of digoxin. Over 2 h, disappearance of erythromycin and vinblastine from the incubation medium was significantly greater from the basolateral than from the apical compartments. In the presence of digoxin, disappearance of both compounds from the basolateral, but not from the apical compartments, was significantly reduced. In contrast, disappearance of testosterone was unaffected by the addition of digoxin, demonstrating that the effect of digoxin on erythromycin and vinblastine disappearance was via inhibition of Pgp function, rather than on CYP3A4 activity. Thus, evidence is provided for Pgp/CYP3A4 co-substrates, Pgp potentiates CYP3A4-mediated drug disappearance during intestinal secretory detoxification.
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http://dx.doi.org/10.1080/10611860412331285224DOI Listing
March 2005

Differential multidrug resistance-associated protein 1 through 6 isoform expression and function in human intestinal epithelial Caco-2 cells.

J Pharmacol Exp Ther 2004 Nov 21;311(2):476-84. Epub 2004 Jun 21.

Institute for Cell and Molecular Biosciences, University of Newcastle, Medical School, Newcastle upon Tyne NE2 4HH, UK.

Multidrug resistance-associated protein (MRP) isoforms 1 through 6 mRNA are expressed in the human intestine and Caco-2 cells. In Caco-2 cells, the rank order for mRNA expression was MRP2 > or = MRP6 > MRP4 > or = MRP3 > MRP1 = MRP5. The functional expression of MRP-like activity was quantified as the efflux of the fluorescent probe calcein from confluent, polarized monolayers of Caco-2 cells. Calcein efflux was sensitive to temperature, energy depletion, and the MRP antagonist MK571 [3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid]. Calcein efflux across the apical membrane of Caco-2 cells exceeded that across the basolateral by approximately 2-fold, correlating with the apical localization of MRP2 visualized by immunocytochemical staining. T84 cells do not express MRP2 and show a predominance of basolateral calcein efflux over apical efflux. MRP3 was localized by immunocytochemical staining to the basolateral membrane. MRP1 staining was not localized to either membrane domain and MRP5 staining was not detected. Thus, basolateral calcein efflux may reflect a function of MRP3 or MRP4 and 6 inferred by their basolateral localization in other tissues. Basolateral, but not apical, calcein efflux was sensitive to glutathione depletion with buthioninesulfoximine, indicating that whereas MRP2-mediated apical efflux is independent of glutathione, basolateral efflux is glutathione-dependent. Benzbromarone, probenecid, pravastatin, and diclofenac were able to inhibit both apical and basolateral calcein efflux. The apical calcein efflux in Caco-2 cells was selectively sensitive to indomethacin and propranolol, but not verapamil or erythromycin, whereas the converse was observed for basal efflux. The differential pharmacological sensitivity of apical (MRP2) and basolateral calcein efflux provides tools for dissecting MRP isoform functional roles.
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http://dx.doi.org/10.1124/jpet.104.068775DOI Listing
November 2004

The influence of DMPK as an integrated partner in modern drug discovery.

Curr Drug Metab 2002 Oct;3(5):527-50

Department of Physical and Metabolic Science, AstraZeneca RD Charnwood, Loughborough, Leics LE11 5RH, UK.

In response to the challenge laid down by advances in other drug discovery functions, DMPK has now established an array of automated, miniaturised in vitro screens, rapid bioanalytical methodologies and in silico tools with which to optimise or predict passive absorption, metabolic clearance and minimise drug-drug interaction potential. The awareness of the pivotal role that physicochemical properties play in the control of many of these processes has been key. This review highlights some of these structure-activity relationships with emphasis on drug absorption, clearance, protein binding and distribution. However, some fundamental processes remain to be elucidated fully, including the in vivo impact of non-specific or futile binding in in vitro screens and the functional significance of intestinal and hepatobiliary transporter proteins. Transgenic animals should soon add value to our understanding of the contribution of transporter proteins to drug bioavailability (intestinal and hepatic drug uptake/efflux) and drug interactions and in validating projections for Man. Future studies should also focus on the evaluation of the various in vitro human CYP induction screens available, with particular emphasis on their predictive value for the clinical scenario.
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http://dx.doi.org/10.2174/1389200023337135DOI Listing
October 2002
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