Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 2.
The continued SAR investigation of 2-amino-8-alkoxy quinolines as melanin concentrating hormone receptor-1 (MCHr1) antagonists is reported. Prior hit-to-lead efforts resulted in the identification of 1 as a robust MCHr1 antagonist. Further delineation of the structural parameters essential for MCHr1-binding affinity of this class of nontraditional GPCR ligands resulted in the identification of compounds such as 33, 34 and 37, which demonstrate single digit nanomolar antagonism of MCHr1-mediated Ca(2+) release. The synthesis and biological evaluation of these compounds are reported.
Vasudevan
Anil
A
Metabolic Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. anil.vasudevan@abbott.com
Wodka
Dariusz
D
Verzal
Mary K
MK
Souers
Andrew J
AJ
Gao
Ju
J
Brodjian
Sevan
S
Fry
Dennis
D
Dayton
Brian
B
Marsh
Kennan C
KC
Hernandez
Lisa E
LE
Ogiela
Christopher A
CA
Collins
Christine A
CA
Kym
Philip R
PR
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis*; D051379:Mice; D011804:Quinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; C491209:Mchr1 protein, mouse; D011804:Quinolines; D017481:Receptors, Somatostatin