Identification of a 5-HT4 receptor antagonist clinical candidate through side-chain modification

  • Bioorg Med Chem Lett. 2005 Mar 15;15(6):1697-700. doi: 10.1016/j.bmcl.2005.01.039.
Robin D Clark  1 ,  Alam Jahangir ,  Muzaffar Alam ,  Cynthia Rocha ,  Lin Lin ,  Bodil Bjorner ,  Khanh Nguyen ,  Carole Grady ,  Timothy J Williams ,  George Stepan ,  Hai Ming Tang ,  Anthony P D W Ford
Affiliations
  • 1. Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94303, USA. [email protected]
PMID: 15745824 DOI: 10.1016/j.bmcl.2005.01.039
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 for the treatment of urinary incontinence.

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