Bis(aminopyrrolidine)-derived ureas (APUs) as potent MCH1 receptor antagonists.
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).
Grey
Jonathan
J
Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
Dyck
Brian
B
Rowbottom
Martin W
MW
Tamiya
Junko
J
Vickers
Troy D
TD
Zhang
Mingzhu
M
Zhao
Liren
L
Heise
Christopher E
CE
Schwarz
David
D
Saunders
John
J
Goodfellow
Val S
VS
D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry* / Q000494:pharmacology*
D011759:Pyrrolidines; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; D014508:Urea