Discovery of Two Clinical Histamine H3 Receptor Antagonists: trans-N-Ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans<

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• 作者：Travis T. Wager ; Betty A. Pettersen ; Anne W. Schmidt ; Douglas K. Spracklin ; Scot Mente ; Todd W. Butler ; Harry Howard ; Jr ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 10, 2011
• 年：2011
• 卷：54
• 期：21
• 页码：7602-7620
• 全文大小：1354K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

The discovery of two histamine H₃ 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, 鈥渂est-in-class鈥?molecules.