title: 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.
abstract: 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.
authors.affiliation: Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. andrew.souers@abbott.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
authors.forename: Michael
authors.initials: M
authors.lastname: Brune
authors.forename: Eugene
authors.initials: E
authors.lastname: Bush
authors.forename: Dariusz
authors.initials: D
authors.lastname: Wodka
authors.forename: Anil
authors.initials: A
authors.lastname: Vasudevan
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Judd
authors.forename: Mathew
authors.initials: M
authors.lastname: Mulhern
authors.forename: Sevan
authors.initials: S
authors.lastname: Brodjian
authors.forename: Brian
authors.initials: B
authors.lastname: Dayton
authors.forename: Robin
authors.initials: R
authors.lastname: Shapiro
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hernandez
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Christine A
authors.initials: CA
authors.lastname: Collins
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
mesh_terms: 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
chemical_list: 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