2. Academic Validation
  3. 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)

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

Affiliation

  • 1 Pfizer Worldwide Research and Development, Groton, CT 06340-5159, USA. travis.t.wager@pfizer.com
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.

Figures
Products