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Discovery of GSK345931A: An EP(1) receptor antagonist with efficacy in preclinical models of inflammatory pain.

Abstract
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
AuthorsAdrian Hall, Susan H Brown, Christopher Budd, Nicholas M Clayton, Gerard M P Giblin, Paul Goldsmith, Thomas G Hayhow, David N Hurst, Alan Naylor, D Anthony Rawlings, Tiziana Scoccitti, Alexander W Wilson, Wendy J Winchester
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 2 Pg. 497-501 (Jan 15 2009) ISSN: 1464-3405 [Electronic] England
PMID19036582 (Publication Type: Journal Article)
Chemical References
  • GSK345931A
  • Ptger1 protein, mouse
  • Ptger1 protein, rat
  • Pyridines
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype
Topics
  • Animals
  • Drug Evaluation, Preclinical
  • Inflammation (drug therapy)
  • Pain (drug therapy)
  • Pyridines (chemistry, pharmacology, therapeutic use)
  • Rats
  • Receptors, Prostaglandin E (antagonists & inhibitors)
  • Receptors, Prostaglandin E, EP1 Subtype
  • Structure-Activity Relationship

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