文摘
The discovery of two histamine H3 antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-036547ass="uu">46) and 7 (PF-036547ass="uu">64) 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, 鈥渂est-in-class鈥?molecules.