1. Academic Validation
  2. Identification of a 5-HT4 receptor antagonist clinical candidate through side-chain modification

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

Affiliation

  • 1 Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94303, USA. robin.clark5@verizon.net
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.

Figures
Products