Discovery of cyclopentane- and cyclohexane-trans-1,3-diamines as potent melanin-concentrating hormone receptor 1 antagonists.
We herein report the optimization of cyclopentane- and cyclohexane-1,3-diamine derivatives as novel and potent MCH-R1 antagonists. Structural modifications of the 2-amino-quinoline and thiophene moieties found in the initial lead compound served to improve its metabolic stability profile and MCH-R1 affinity, and revealed unprecedented SAR when compared to other 2-amino-quinoline-containing MCH-R1 antagonists.
Giordanetto
Fabrizio
F
Lead Generation, Computational Chemistry, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden. fabrizio.giordanetto@astrazeneca.com
Karlsson
Olle
O
Lindberg
Jan
J
Larsson
Lars-Olof
LO
Linusson
Anna
A
Evertsson
Emma
E
Morgan
David G A
DG
Inghardt
Tord
T
D003510:Cyclohexanes / Q000737:chemistry*; D003517:Cyclopentanes / Q000737:chemistry*; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*
D003510:Cyclohexanes; D003517:Cyclopentanes; D003959:Diamines; C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin; C506365:Cyclohexane