Bis(aminopyrrolidine)-derived ureas (APUs) as potent MCH1 receptor antagonists

Jonathan Grey; Brian Dyck; Martin W Rowbottom; Junko Tamiya; Troy D Vickers; Mingzhu Zhang; Liren Zhao; Christopher E Heise; David Schwarz; John Saunders; Val S Goodfellow

doi:10.1016/j.bmcl.2004.12.036

Bis(aminopyrrolidine)-derived ureas (APUs) as potent MCH1 receptor antagonists

Bioorg Med Chem Lett. 2005 Feb 15;15(4):999-1004. doi: 10.1016/j.bmcl.2004.12.036.

Authors

Jonathan Grey¹, Brian Dyck, Martin W Rowbottom, Junko Tamiya, Troy D Vickers, Mingzhu Zhang, Liren Zhao, Christopher E Heise, David Schwarz, John Saunders, Val S Goodfellow

Affiliation

¹ Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

PMID: 15686900
DOI: 10.1016/j.bmcl.2004.12.036

Abstract

Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).

MeSH terms

Dose-Response Relationship, Drug
Drug Design
Humans
Pyrrolidines / chemistry
Pyrrolidines / pharmacology
Receptors, Pituitary Hormone / antagonists & inhibitors*
Stereoisomerism
Structure-Activity Relationship
Urea / chemistry*
Urea / pharmacology*

Substances

Pyrrolidines
Receptors, Pituitary Hormone
melanin-concentrating hormone receptor
Urea