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

Fragment-Based Lead Discovery of a Novel Class of Small Molecule Inhibitors of Neuropeptide B/W Receptor Subtype 1 (GPR7). Bioorg Med Chem Lett. 2020 Sep 05;:127510 Authors: Moningka R, Anthony Romero F, Hastings NB, Guo Z, Wang M, Di Salvo J, Li Y, Trusca D, Deng Q, Tong V, Terebetski JL, Ball RG, Ujjainwalla F 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. PMID: 32898693 [PubMed - as supplied by publisher]
Source: Bioorganic and Medicinal Chemistry Letters - Category: Chemistry Authors: Tags: Bioorg Med Chem Lett Source Type: research