Discovery of 1,3-disubstituted-1H-pyrrole derivatives as potent melanin-concentrating hormone receptor 1 (MCH-R1) antagonists.
A series of 1,3-disubstituted-1H-pyrrole-based antagonists of the human Melanin-Concentrating Hormone Receptor 1 (h-MCH-R1) are reported. High-throughput screening of the AstraZeneca compound collection yielded 1, a hit with moderate affinity towards MCH-R1. Subsequent structural manipulations and SAR analysis served to rationalize potency requirements, and 12 was identified as a novel, functional MCH-R1 antagonist with favorable pharmacokinetic properties.
Berglund
Susanne
S
Medicinal Chemistry, AstraZeneca R&D Mölndal, Pepparedsleden 1, SE-431 83, Mölndal, Sweden.
Egner
Bryan J
BJ
Gradén
Henrik
H
Gradén
Joakim
J
Morgan
David G A
DG
Inghardt
Tord
T
Giordanetto
Fabrizio
F
D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D051379:Mice; D011758:Pyrroles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; C103263:MCHR1 protein, human; D011758:Pyrroles; D017481:Receptors, Somatostatin