5-(pyridinon-1-yl)indazoles and 5-(furopyridinon-5-yl)indazoles as MCH-1 antagonists.
A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents. Structural modification of the 5-(pyridinon-1-yl)indazoles to give 5-(furopyridinon-5-yl)indazoles provided compounds with enhanced pharmacokinetic properties and improved efficacy.
Surman
Matthew D
MD
AMRI, 26 Corporate Circle, Albany, NY 12212-5098, USA. matthew.surman@amriglobal.com
Freeman
Emily E
EE
Grabowski
James F
JF
Hadden
Mark
M
Henderson
Alan J
AJ
Jiang
Guowei
G
Jiang
Xiaowu May
XM
Luche
Michele
M
Khmelnitsky
Yuri
Y
Vickers
Steven
S
Viggers
Jean
J
Cheetham
Sharon
S
Guzzo
Peter R
PR
D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000139:chemically induced; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000493:pharmacokinetics / 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; D051638:Ether-A-Go-Go Potassium Channels; D007191:Indazoles; C496884:KCNH1 protein, human; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor