Identification of a 5-HT 4 receptor antagonist clinical candidate through side-chain modification

…, A Jahangir, M Alam, C Rocha, L Lin, B Bjorner…

Index: Clark, Robin D.; Jahangir, Alam; Alam, Muzaffar; Rocha, Cynthia; Lin, Lin; Bjorner, Bodil; Nguyen, Khanh; Grady, Carole; Williams, Timothy J.; Stepan, George; Tang, Hai Ming; Ford, Anthony P.D.W. Bioorganic and Medicinal Chemistry Letters, 2005 , vol. 15, # 6 p. 1697 - 1700

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Citation Number: 3

Abstract

Replacement of the N-butyl side-chain of lead 5-HT4 receptor antagonist 2 with propanesulfonylpiperidinyl, morpholinyl, and piperazinyl groups led to higher affinity analogs 4–6. In vitro drug metabolism screens and cassette pharmacokinetic studies in the dog led to identification of the N-methylpiperazinyl analog (6b), which displayed pharmacokinetic, selectivity, and safety parameters sufficient for advancement to the clinic ...