Tetrahydrocarboline analogs as MCH-1 antagonists.
A new series of tetrahydrocarbolines with potent MCH-1 antagonist activity were synthesized, using a conformationally constrained design approach towards optimizing pharmacokinetic properties. Two compounds from this series were progressed to a 5-day diet-induced obesity mouse screening model to evaluate their potential as weight loss agents. Both compounds produced a highly significant reduction in weight, which was attributed to their improved pharmacokinetic profile.
AMRI, 26 Corporate Circle, Albany, NY 12212-5098, USA. alan.henderson@amriglobal.com
Alan J
AJ
Henderson
Dustin
D
Deering
James F
JF
Grabowski
Mark
M
Hadden
Xiaowu
X
Jiang
Yuri
Y
Khmelnitsky
Michele
M
Luche
Matthew D
MD
Surman
Sharon
S
Cheetham
Steven
S
Vickers
Jean
J
Viggers
Peter R
PR
Guzzo
D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002243:Carbolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; D002243:Carbolines; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor