1区 · 医学
Article
作者: Spracklin, Douglas K. ; Lettiere, Daniel J. ; Wager, Travis T. ; Marcek, John M. ; Freeman, Jody K. ; Rollema, Hans ; Howard, Harry ; Nedza, Frank M. ; Aubrecht, Jiri ; Rubitski, David M. ; Butler, Todd W. ; James, Larry C. ; Banker, Michael J. ; Cook, Karen W. ; Homiski, Michael L. ; Raggon, Jeffrey W. ; Munzner, Jennifer B. ; Chandrasekaran, Rama Y. ; Iredale, Philip A. ; Cianfrogna, Julie ; Wong, Diane F. ; Pettersen, Betty A. ; Nelson, Frederick R. ; Schmidt, Anne W. ; Mente, Scot ; Chatman, Linda A.
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.