Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors
Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors
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DOI：
10.1021/jm502009h
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发表时间：
2015-04-23
影响因子：
7.3
通讯作者：
Ulrich, John C.
中科院分区：
文献类型：
--
作者：
Haffner, Curt D.;Becherer, J. David;Ulrich, John C.
合成了一系列的噻唑喹酮类化合物，发现它们对CD38具有很强的抑制活性。其中几个化合物也被证明具有良好的药代动力学特性，并证明有能力提高血浆、肝脏和肌肉组织中的NAD水平。特别是，化合物78c被喂给饮食诱导肥胖(DIO)C57BL6小鼠，在2小时的时间点上，肝脏中的NAD和肌肉中的NAD和GT；分别是对照组的5倍和1.2倍。本文中描述的化合物在文献中描述的任何小分子中具有最强的CD38抑制活性。这些抑制剂应该可以更详细地评估通过抑制CD38而导致的NAD升高如何影响NAD缺陷状态的生理。
A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver, and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold in liver and >1.2-fold in muscle versus control animals at a 2 h time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states.