title: SAR analysis of novel non-peptidic NPBWR1 (GPR7) antagonists.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Guerrero
authors.forename: Mariangela
authors.initials: M
authors.lastname: Urbano
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Schaeffer
authors.forename: Steven
authors.initials: S
authors.lastname: Brown
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D005449:Fluorenes / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C579651:5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one; C581837:5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one; D000700:Analgesics; D005449:Fluorenes; C485722:NPBWR1 protein, human; D010455:Peptides; D011724:Pyridazines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide