title: Identification of a 5-HT4 receptor antagonist clinical candidate through side-chain modification.
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.
authors.affiliation: Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94303, USA. robin.clark5@verizon.net
authors.forename: Robin D
authors.initials: RD
authors.lastname: Clark
authors.forename: Alam
authors.initials: A
authors.lastname: Jahangir
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Alam
authors.forename: Cynthia
authors.initials: C
authors.lastname: Rocha
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Bodil
authors.initials: B
authors.lastname: Bjorner
authors.forename: Khanh
authors.initials: K
authors.lastname: Nguyen
authors.forename: Carole
authors.initials: C
authors.lastname: Grady
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Williams
authors.forename: George
authors.initials: G
authors.lastname: Stepan
authors.forename: Hai Ming
authors.initials: HM
authors.lastname: Tang
authors.forename: Anthony P D W
authors.initials: AP
authors.lastname: Ford
mesh_terms: D000818:Animals; D004285:Dogs; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D051381:Rats; D058832:Serotonin 5-HT4 Receptor Antagonists; D013329:Structure-Activity Relationship; D013552:Swine; D013556:Swine, Miniature
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; D058832:Serotonin 5-HT4 Receptor Antagonists