Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10–100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models.

从4-氨基-8-喹啉羧酰胺铅1a和支架跃迁到化学上更易处理的喹唑啉，利用结构活性关系和构象约束力对喹唑啉环的2个取代基进行系统的探索，从而鉴定出39种新的CD38抑制剂。这些类似物中的八种是有效的人类CD38抑制剂的10-100倍，其中包括一位数纳摩尔抑制剂1am。这些分子中的几种还表现出相对于hERG活性改善的治疗指数。代表性的类似物1r在体内表现出合适的药代动力学参数动物研究，包括中等清除率和良好的口服生物利用度。这些抑制剂化合物将有助于探索CD38的酶功能，并进一步研究NAD增强在代谢性疾病模型中的治疗意义。