Identification of 2-(4-benzyloxyphenyl)-N- [1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide, an orally efficacious melanin-concentrating hormone receptor 1 antagonist for the treatment of obesity.
Optimization of a high-throughput screening hit against melanin-concentrating hormone receptor 1 (MCHr1) led to the discovery of 2-(4-benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide (7a). This compound was found to be a high-affinity ligand for MCHr1 and a potent inhibitor of MCH-mediated Ca(2+) release, showed good plasma and CNS exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHr1 antagonist that is efficacious upon oral dosing in a chronic model of weight loss.
Souers
Andrew J
AJ
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. andrew.souers@abbott.com
Gao
Ju
J
Brune
Michael
M
Bush
Eugene
E
Wodka
Dariusz
D
Vasudevan
Anil
A
Judd
Andrew S
AS
Mulhern
Mathew
M
Brodjian
Sevan
S
Dayton
Brian
B
Shapiro
Robin
R
Hernandez
Lisa E
LE
Marsh
Kennan C
KC
Sham
Hing L
HL
Collins
Christine A
CA
Kym
Philip R
PR
D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002908:Chronic Disease; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
C499136:2-(4-benzyloxyphenyl)-N-(1-(2-pyrrolidin-1-ylethyl)-1H-indazol-6-yl)acetamide; D000081:Acetamides; D019440:Anti-Obesity Agents; D007191:Indazoles; C491209:Mchr1 protein, mouse; D011759:Pyrrolidines; D017481:Receptors, Somatostatin; D002118:Calcium