SAR study of bicyclo[4.1.0]heptanes as melanin-concentrating hormone receptor R1 antagonists: taming hERG.
To improve the ex vivo potency of MCH inhibitor 1a and to address its hERG liability, a structure-activity study was carried out, focusing on three regions of the lead structure. Introduction of new side chains with basic nitrogen improved in vitro and ex vivo bindings. Many potent compounds with K(i)<10nM were discovered (compounds 6a-j) and several compounds (14-17) had excellent ex vivo binding at 6h and 24h. Attenuating the basicity of nitrogen on the side chain, and in particular, introduction of a polar group such as aminomethyl on the distal phenyl ring significantly lowered the hERG activity. Further replacement of the distal phenyl group with heteroaryl groups in the cyclohexene series provided compounds such as 28l with excellent ex vivo activity with much reduced hERG liability.
Su
Jing
J
Department of Chemical Research, Schering-Plough Research Institute K15 2545, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
McKittrick
Brian A
BA
Tang
Haiqun
H
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
Li
Cheng
C
Liu
Tongtong
T
D000818:Animals; D003508:Cycloheptanes / Q000737:chemistry* / Q000493:pharmacokinetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG
D003508:Cycloheptanes; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D011979:Receptors, Pituitary Hormone; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C092274:melanin-concentrating hormone receptor