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
  • 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. [email protected]
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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