Synthesis of novel bicyclo[4.1.0]heptane and bicyclo[3.1.0]hexane derivatives as melanin-concentrating hormone receptor R1 antagonists.
To address the hERG liability of MCHR1 antagonists such as 1 and 2, new analogs such as 4 and 5 that incorporated a polar heteroaryl group were designed and synthesized. Biological evaluation confirmed that these new analogs retained MCH R1 activity with greatly attenuated hERG liabilities as indicated in the Rb efflux assay.
Su
Jing
J
Department of Chemical Research, Schering-Plough Research Institute K15 2545, Kenilworth, NJ 07033, USA. jing.su@spcorp.com
Tang
Haiqun
H
McKittrick
Brian A
BA
Gu
Huizhong
H
Guo
Tao
T
Qian
Gang
G
Burnett
Duane A
DA
Clader
John W
JW
Greenlee
William J
WJ
Hawes
Brian E
BE
O'neill
Kim
K
Spar
Brian
B
Weig
Blair
B
Kowalski
Timothy
T
Sorota
Steve
S
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005399:Fishes; D006536:Heptanes / Q000737:chemistry*; D006586:Hexanes / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*
D006536:Heptanes; D006586:Hexanes; C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin