Design, Synthesis and SAR Analysis of Novel Potent and Selective Small Molecule Antagonists of NPBWR1 (GPR7)

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2012 Oct 20

PMID 23079522

Citations 3

Authors

Mariangela Urbano

Miguel Guerrero

Jian Zhao

Subash Velaparthi

S Adrian Saldanha

Peter Chase

Zhiwei Wang

Olivier Civelli

Peter Hodder

Marie-Therese Schaeffer

Steven Brown

Hugh Rosen

Edward Roberts

Affiliations

Soon will be listed here.

Abstract

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.

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