Article

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

Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94303, USA.
Bioorganic & Medicinal Chemistry Letters (impact factor: 2.55). 04/2005; 15(6):1697-700. DOI:10.1016/j.bmcl.2005.01.039 pp.1697-700
Source: PubMed

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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Keywords

advancement
 
cassette pharmacokinetic studies
 
displayed pharmacokinetic
 
higher affinity analogs 4-6
 
lead 5-HT4 receptor antagonist 2
 
N-methylpiperazinyl analog
 
safety parameters sufficient
 
selectivity
 
urinary incontinence
 
vitro drug metabolism screens
 

Robin D Clark