SAR analysis of novel non-peptidic NPBWR1 (GPR7) antagonists.
Basic Information
ID: ALA2311420
Journal: Bioorg Med Chem Lett
Title: SAR analysis of novel non-peptidic NPBWR1 (GPR7) antagonists.
Authors: Guerrero M, Urbano M, Schaeffer MT, Brown S, Rosen H, Roberts E.
Abstract: In this Letter we report on the advances in our NPBWR1 antagonist program aimed at optimizing the 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule previously obtained from a high-throughput screening (HTS)-derived hit. Synthesis and structure-activity relationships (SAR) studies around the 3,5-dimethylphenyl and 4-methoxyphenyl regions resulted in the identification of a novel series of non-peptidic submicromolar NPBWR1 antagonists based on a 5-chloro-4-(4-alkoxyphenoxy)-2-(benzyl)pyridazin-3(2H)-one chemotype. Amongst them, 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one 9h (CYM50769) inhibited NPW activation of NPBWR1 with a submicromolar IC(50), and displayed high selectivity against a broad array of off-targets with pharmaceutical relevance. Our medicinal chemistry study provides innovative non-peptidic selective NPBWR1 antagonists that may enable to clarify the biological role and therapeutic utility of the target receptor in the regulation of feeding behavior, pain, stress, and neuroendocrine function.
CiteXplore: 23287738
DOI: 10.1016/j.bmcl.2012.12.030
Patent ID: ┄