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Fragment-Based Lead Discovery of a Novel Class of Small Molecule Inhibitors of Neuropeptide B/W Receptor Subtype 1 (GPR7).

Authors
  • Moningka, Remond1
  • Anthony Romero, F2
  • Hastings, Nicholas B3
  • Guo, Zhiqiang2
  • Wang, Ming2
  • Di Salvo, Jerry4
  • Li, Ying4
  • Trusca, Dorina4
  • Deng, Qiaoling5
  • Tong, Vincent6
  • Terebetski, Jenna L7
  • Ball, Richard G8
  • Ujjainwalla, Feroze2
  • 1 Merck & Co., Inc., Department of Medicinal Chemistry, PO Box 2000, Rahway, NJ 07065, USA. Electronic address: [email protected]
  • 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.
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Sep 05, 2020
Pages
127510–127510
Identifiers
DOI: 10.1016/j.bmcl.2020.127510
PMID: 32898693
Source
Medline
Keywords
Language
English
License
Unknown

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 6,700-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 differentiate class of compounds with which to form a better appreciation of the pharmacology and physiological roles of this central neuropeptide system. Copyright © 2020 Elsevier Ltd. All rights reserved.

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