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.

在这里，我们报告发现了从基于片段的屏幕中鉴定出的新型NPBWR1拮抗剂。化合物1（cAMP IC ₅₀  = 250 µM； LE = 0.29）作为最初的产物出现。通过SAR-by-catalogue和化学修饰进一步优化1，可产生21a（cAMP IC ₅₀  = 30 nM； LE = 0.39），其片段1的效价提高了6700倍。出乎意料的是，对化合物21a进行Schild分析表明，对NPW介导的对cAMP积累的影响的体外抑制作用是饱和的，并且化合物21a在动力学结合研究中，NPBWR1的剂量依赖性地增加了[125I] -hNPW23的解离速率常数。总体而言，这些数据与经典的可克服的正构抑制机制不一致。因此，本文报道的苯并咪唑抑制剂可以代表机械上分化的一类化合物，通过它们可以更好地理解该中枢神经肽系统的药理作用和生理作用。