Discovery of Two Clinical Histamine H ₃ Receptor Antagonists: <i>trans</i> - <i>N</i> -Ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and <i>trans</i> -3-Fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]- <i>N</i> -(2-methylpropyl)cyclobutanecarboxamide (PF-03654764)

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.