Synthesis and evaluation of urea-based indazoles as melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity.
A series of urea-based N-1-(2-aminoethyl)-indazoles was synthesized and evaluated for melanin-concentrating hormone receptor 1 (MCHr1) antagonism in both binding and functional assays. Several compounds that acted as MCHr1 antagonists were identified, and optimization afforded a compound with excellent binding affinity, good functional potency, and oral efficacy in a chronic model for weight loss in diet-induced obese mice.
Souers
Andrew J
AJ
Metabolic Disease Research, Abbott Laboratories, Abbott Park, IL 60064, USA. andrew.souers@abbott.com
Gao
Ju
J
Wodka
Dariusz
D
Judd
Andrew S
AS
Mulhern
Mathew M
MM
Napier
James J
JJ
Brune
Michael E
ME
Bush
Eugene N
EN
Brodjian
Sevan J
SJ
Dayton
Brian D
BD
Shapiro
Robin
R
Hernandez
Lisa E
LE
Marsh
Kennan C
KC
Sham
Hing L
HL
Collins
Christine A
CA
Kym
Philip R
PR
D000818:Animals; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry*
D007191:Indazoles; C491209:Mchr1 protein, mouse; D017481:Receptors, Somatostatin; D014508:Urea