title: Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 3.
abstract: 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.
authors.affiliation: Metabolic Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park IL 60064, USA. andrew.souers@abbott.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.forename: Dariusz
authors.initials: D
authors.lastname: Wodka
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
authors.forename: Jared C
authors.initials: JC
authors.lastname: Lewis
authors.forename: Anil
authors.initials: A
authors.lastname: Vasudevan
authors.forename: Sevan
authors.initials: S
authors.lastname: Brodjian
authors.forename: Brian
authors.initials: B
authors.lastname: Dayton
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ogiela
authors.forename: Dennis
authors.initials: D
authors.lastname: Fry
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hernandez
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Christine A
authors.initials: CA
authors.lastname: Collins
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
mesh_terms: 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
chemical_list: D019440:Anti-Obesity Agents; C491209:Mchr1 protein, mouse; D011804:Quinolines; D017481:Receptors, Somatostatin