Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38
Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38
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DOI：
10.1021/acs.jmedchem.5b00992
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发表时间：
2015-09-10
影响因子：
7.3
通讯作者：
Ulrich, John C.
中科院分区：
文献类型：
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作者：
Becherer, J. David;Boros, Eric E.;Ulrich, John C.
从微摩尔级的8 - 喹啉甲酰胺高通量筛选命中物1a出发，对喹啉环的4 -、6 - 和8 - 位取代基的构效关系（SAR）进行系统探究，鉴定出了效力约高10 - 100倍的人CD38抑制剂。这些分子中的若干个还展现出适用于体内动物研究的药代动力学参数，包括低清除率和良好的口服生物利用度。在饮食诱导肥胖（DIO）的C57BL / 6小鼠模型中，其中两种CD38抑制剂1ah和1ai被证明可提高肝脏和肌肉中的烟酰胺腺嘌呤二核苷酸（NAD）组织水平。这些抑制剂工具化合物将使CD38酶的进一步生物学研究以及在烟酰胺腺嘌呤二核苷酸异常低的疾病模型中对烟酰胺腺嘌呤二核苷酸增强的治疗意义的研究成为可能。
Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit la, a systematic exploration of the structure activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAB tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.