Discovery of two clinical histamine H(3) receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764)

  • J Med Chem. 2011 Nov 10;54(21):7602-20. doi: 10.1021/jm200939b.
Travis T Wager  1 ,  Betty A Pettersen ,  Anne W Schmidt ,  Douglas K Spracklin ,  Scot Mente ,  Todd W Butler ,  Harry Howard ,  Daniel J Lettiere ,  David M Rubitski ,  Diane F Wong ,  Frank M Nedza ,  Frederick R Nelson ,  Hans Rollema ,  Jeffrey W Raggon ,  Jiri Aubrecht ,  Jody K Freeman ,  John M Marcek ,  Julie Cianfrogna ,  Karen W Cook ,  Larry C James ,  Linda A Chatman ,  Philip A Iredale ,  Michael J Banker ,  Michael L Homiski ,  Jennifer B Munzner ,  Rama Y Chandrasekaran
Affiliations
  • 1. Pfizer Worldwide Research and Development, Groton, CT 06340-5159, USA. [email protected]
PMID: 21928839 DOI: 10.1021/jm200939b
Abstract

The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.

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