Discovery of sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (GSK269984A) an EP1 receptor antagonist for the treatment of inflammatory pain

Hall, Adrian; Billinton, Andy; Brown, Susan H.; Chowdhury, Ashim; Clayton, Nick M.; Giblin, Gerard M.P.; Gibson, Mairi; Goldsmith, Paul; Hurst, David N.; Naylor, Alan; Peet, Caroline; Scoccitti, Tiziana; Wilson, Alexander W.; Winchester, Wendy J.

doi:10.1016/j.bmcl.2009.02.112

Cited by 17 publications

(15 citation statements)

References 39 publications

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“…In drug metabolism and pharmacokinetic (DMPK) studies the in vitro metabolic stability of GSK269984A was profiled using microsomes derived from mouse, rat, dog, monkey and human liver.This revealed a low intrinsic clearance (CLi) across all species (Յ 0.7 ml min -1 g -1 liver) [16]. Further studies, undertaken with hepatocytes and S9 fraction to include phase 2 metabolic pathways, similarly provided evidence of low CLi and low metabolic turnover across all tested species.…”

Section: Introductionmentioning

confidence: 99%

“…GSK269984A has been shown to possess analgesic efficacy in models of inflammation [16]. In the rat complete Freund's adjuvant (CFA) model of inflammatory pain, orally administered GSK269984A produced a dose-dependent reversal of hypersensitivity (ED50 2.6 mg kg -1 ).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, the CLi data for GSK269984A were found not to predict the in vivo PK profile observed across three pre-clinical species. These data showed GSK269984A blood clearance (CLb) to be high in the monkey and moderate in the rat and dog, which was reflected in the respective species terminal halflives [16]. Oral bioavailability (relatively high in the rat (94%), moderate in the dog (39%) and low in the monkey (7%) [16]) was therefore considered to be limited by firstpass hepatic extraction in each of the species.…”

Section: Introductionmentioning

confidence: 99%

“…These data showed GSK269984A blood clearance (CLb) to be high in the monkey and moderate in the rat and dog, which was reflected in the respective species terminal halflives [16]. Oral bioavailability (relatively high in the rat (94%), moderate in the dog (39%) and low in the monkey (7%) [16]) was therefore considered to be limited by firstpass hepatic extraction in each of the species. Whilst the solubility and permeability data suggested that the compound should diffuse well across cell membranes, and there was no evidence that GSK269984A is a P-glycoprotein (P-gp) substrate, the steady-state volume of distribution (Vss) differed across the preclinical species being highest in the rat (circa 2.1 l kg -1 ) and similar in the dog and monkey (circa 0.6 l kg -1 ) even though the plasma protein binding was comparable across all three species (99.9% (rat and human).…”

Section: Introductionmentioning

confidence: 99%

“…The medicinal chemistry and lead optimization programme leading to the discovery and selection of GSK269984A (sodium 6-[(5-chloro-2-{[(4-chloro-2-fluoro phenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate: see Figure 1) as a candidate for development as a treatment for inflammatory pain has been reported previously together with the key in vitro and in vivo characteristics at the time of candidate selection [16]. In vitro recombinant assay systems have shown GSK269984A to be a potent, functional competitive antagonist at the human EP1 receptor with nanomolar activity.…”

Section: Introductionmentioning

confidence: 99%

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Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Ostenfeld

Beaumont

Bullman

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The microdose administration of novel drug candidates to humans in early development is currently undergoing evaluation as a cost‐efficient approach to the early assessment of pharmacokinetics (PK) before the commitment of resources required to support formal phase 1 studies.• The microdose approach assumes that PK can be extrapolated linearly over the full range of exposures achieved with sub‐pharmacological doses up to the therapeutic dose range.• Few microdose studies have been undertaken in the context of pharmaceutical drug development and their precise role in the selection of candidates for further clinical evaluation at therapeutic doses has yet to be fully substantiated.WHAT THIS STUDY ADDS• The present study describes the elective application of a human microdose study with a novel EP1 receptor antagonist, GSK269984A, to address a critical development liability posed by uncertainty with respect to the predicted human PK profile.• Microdose data revealed a favourable PK profile, consistent with a clinically acceptable dosing regimen. These data support the value of undertaking a microdose study early in the drug discovery process to facilitate risk evaluation and to enable decision‐making.AIM The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP1 antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg).METHOD GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography‐tandem mass spectrometry method following solid phase extraction.RESULTS Following the i.v. microdose, the geometric mean values for clearance (CL), steady‐state volume of distribution (Vss) and terminal elimination half‐life (t1/2) of GSK269984A were 9.8 l h−1, 62.8 l and 8.2 h. Cmax and AUC(0,∞) were 3.2 ng ml−1 and 10.2 ng ml−1 h, respectively; the corresponding oral parameters were 1.8 ng ml−1 and 9.8 ng ml−1 h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre‐clinical species (rat, dog and monkey).CONCLUSION For drug development programmes characterized by inconsistencies between pre‐clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%