Fragment-based lead discovery of a novel class of small molecule antagonists of neuropeptide B/W receptor subtype 1 (GPR7)

Remond Moningka; F Anthony Romero; Nicholas B Hastings; Zhiqiang Guo; Ming Wang; Jerry Di Salvo; Ying Li; Dorina Trusca; Qiaoling Deng; Vincent Tong; Jenna L Terebetski; Richard G Ball; Feroze Ujjainwalla

doi:10.1016/j.bmcl.2020.127510

Fragment-based lead discovery of a novel class of small molecule antagonists of neuropeptide B/W receptor subtype 1 (GPR7)

Bioorg Med Chem Lett. 2020 Dec 1;30(23):127510. doi: 10.1016/j.bmcl.2020.127510. Epub 2020 Sep 6.

Authors

Affiliations

¹ Merck & Co., Inc., Department of Medicinal Chemistry, PO Box 2000, Rahway, NJ 07065, USA. Electronic address: remond_moningka@merck.com.
² Merck & Co., Inc., Department of Medicinal Chemistry, PO Box 2000, Rahway, NJ 07065, USA.
³ Merck & Co., Inc., Department of Neuroscience and Ophthalmology, Kenilworth, NJ 07033, USA.
⁴ Merck & Co., Inc., Department of In Vitro Pharmacology, PO Box 2000, Rahway, NJ 07065, USA.
⁵ Merck & Co., Inc., Department of Chemistry Modeling and Informatics, PO Box 2000, Rahway, NJ 07065, USA.
⁶ Merck & Co., Inc., Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, PO Box 2000, Rahway, NJ 07065, USA.
⁷ Merck & Co., Inc., Department of Basic Pharmaceutical Sciences, PO Box 2000, Rahway, NJ 07065, USA.
⁸ Merck & Co., Inc., Department of Analytical Chemistry, PO Box 2000, Rahway, NJ 07065, USA.

PMID: 32898693
DOI: 10.1016/j.bmcl.2020.127510

Abstract

Here, we report the discovery of a new class of NPBWR1 antagonists identified from a fragment-based screen. Compound 1 (cAMP IC₅₀ = 250 µM; LE = 0.29) emerged as an initial hit. Further optimization of 1 by SAR-by-catalogue and chemical modification produced 21a (cAMP IC₅₀ = 30 nM; LE = 0.39) with a 6700-fold increase in potency from fragment 1. Somewhat surprisingly, Schild analysis of compound 21a suggested that in vitro inhibition of NPW-mediated effects on upon cAMP accumulation were saturable, and that compound 21a dose-dependently increased [125I]-hNPW23 dissociation rate constants from NPBWR1 in kinetic binding studies. Collectively, these data are inconsistent with a classic surmountable, orthosteric mechanism of inhibition. The benzimidazole inhibitors reported herein may therefore represent a mechanistically differentiated class of compounds with which to form a better appreciation of the pharmacology and physiological roles of this central neuropeptide system.

Keywords: Anti-obesity; G protein-coupled receptor; GPR7; NPBWR1; Schild plot analysis.

MeSH terms

Animals
Benzimidazoles / chemical synthesis
Benzimidazoles / pharmacology*
CHO Cells
Cricetulus
Drug Discovery
Humans
Molecular Structure
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Receptors, Neuropeptide / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Benzimidazoles
NPBWR1 protein, human
Receptors, G-Protein-Coupled
Receptors, Neuropeptide