Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 3.
Prior SAR studies on 2-amino-8-alkoxyquinoline MCHr1 antagonists demonstrated that compounds with acyclic amide-containing sidechains displayed exceptional binding and functional potency, but negligible CNS penetration. Related analogs with acyclic benzylamine-containing sidechains showed greatly improved CNS exposure, but suffered in functional potency. In this report, we demonstrate that cyclization of these benzylic amine sidechains affords compounds that combine the best elements of potency and CNS penetration among this class of antagonists. This is exemplified by compound 21, which has sub-nanomolar MCHr1 binding affinity, good functional potency, and excellent CNS exposure over 24h.
Souers
Andrew J
AJ
Metabolic Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park IL 60064, USA. andrew.souers@abbott.com
Wodka
Dariusz
D
Gao
Ju
J
Lewis
Jared C
JC
Vasudevan
Anil
A
Brodjian
Sevan
S
Dayton
Brian
B
Ogiela
Christopher A
CA
Fry
Dennis
D
Hernandez
Lisa E
LE
Marsh
Kennan C
KC
Collins
Christine A
CA
Kym
Philip R
PR
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis*; D001921:Brain / Q000378:metabolism; D051379:Mice; D011804:Quinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; C491209:Mchr1 protein, mouse; D011804:Quinolines; D017481:Receptors, Somatostatin