Design, synthesis and SAR analysis of novel potent and selective small molecule antagonists of NPBWR1 (GPR7).
Novel small molecule antagonists of NPBWR1 (GPR7) are herein reported. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 5-chloro-4-(4-methoxyphenoxy)-2-(p-tolyl)pyridazin-3(2H)-one as a NPBWR1 hit antagonist with micromolar activity. Design, synthesis and structure-activity relationships study of the HTS-derived hit led to the identification of 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule with submicromolar antagonist activity at the target receptor and high selectivity against a panel of therapeutically relevant off-target proteins. This lead molecule may provide a pharmacological tool to clarify the molecular basis of the in vivo physiological function and therapeutic utility of NPBWR1 in diverse disease areas including inflammatory pain and eating disorders.
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
Mariangela
M
Urbano
Miguel
M
Guerrero
Jian
J
Zhao
Subash
S
Velaparthi
S Adrian
SA
Saldanha
Peter
P
Chase
Zhiwei
Z
Wang
Olivier
O
Civelli
Peter
P
Hodder
Marie-Therese
MT
Schaeffer
Steven
S
Brown
Hugh
H
Rosen
Edward
E
Roberts
D015195:Drug Design; D006801:Humans; D011485:Protein Binding; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
C579651:5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one; C485722:NPBWR1 protein, human; D011724:Pyridazines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D054852:Small Molecule Libraries; C062482:pyridazine