Synthesis and structure-activity relationships of retro bis-aminopyrrolidine urea (rAPU) derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1). Part 2.
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
Hudson
Sarah
S
Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. shudson@neurocrine.com
Kiankarimi
Mehrak
M
Rowbottom
Martin W
MW
Vickers
Troy D
TD
Wu
Dongpei
D
Pontillo
Joseph
J
Ching
Brett
B
Dwight
Wesley
W
Goodfellow
Val S
VS
Schwarz
David
D
Heise
Christopher E
CE
Madan
Ajay
A
Wen
Jenny
J
Ban
William
W
Wang
Hua
H
Wade
Warren S
WS
D000818:Animals; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
C491208:MCHR1 protein, rat; D011759:Pyrrolidines; D017481:Receptors, Somatostatin; C514080:bis-aminopyrrolidine urea; D014508:Urea