Identification of a 5-HT4 receptor antagonist clinical candidate through side-chain modification.
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.
Clark
Robin D
RD
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94303, USA. robin.clark5@verizon.net
Jahangir
Alam
A
Alam
Muzaffar
M
Rocha
Cynthia
C
Lin
Lin
L
Bjorner
Bodil
B
Nguyen
Khanh
K
Grady
Carole
C
Williams
Timothy J
TJ
Stepan
George
G
Tang
Hai Ming
HM
Ford
Anthony P D W
AP
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
D006574:Heterocyclic Compounds, 2-Ring; D058832:Serotonin 5-HT4 Receptor Antagonists