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Bioorg Med Chem Lett. 2008 Jun 15;18(12):3500-3. doi: 10.1016/j.bmcl.2008.05.027. Epub 2008 May 10.

Development of potent and selective small-molecule human Urotensin-II antagonists.

Author information

1
Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA. jeff.j.mcatee@gsk.com

Abstract

This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.

PMID:
18502123
DOI:
10.1016/j.bmcl.2008.05.027
[Indexed for MEDLINE]

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