2. Academic Validation
  3. Development of potent and selective small-molecule human Urotensin-II antagonists

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

  • Bioorg Med Chem Lett. 2008 Jun 15;18(12):3500-3. doi: 10.1016/j.bmcl.2008.05.027.
John J McAtee 1,  Jason W Dodson,  Sarah E Dowdell,  Gerald R Girard,  Krista B Goodman,  Mark A Hilfiker,  Clark A Sehon,  Deyou Sha,  Gren Z Wang,  Ning Wang,  Andrew Q Viet,  Daohua Zhang,  Nambi V Aiyar,  David J Behm,  Luz H Carballo,  Christopher A Evans,  Harvey E Fries,  Rakesh Nagilla,  Theresa J Roethke,  Xiaoping Xu,  Catherine C K Yuan,  Stephen A Douglas,  Michael J Neeb
Affiliations

Affiliation

  • 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
PMID: 18502123 DOI: 10.1016/j.bmcl.2008.05.027
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.

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