Haffner Curt D, Becherer J David, Boros Eric E, Cadilla Rodolfo, Carpenter Tiffany, Cowan David, Deaton David N, Guo Yu, Harrington Wallace, Henke Brad R, Jeune Michael R, Kaldor Istvan, Milliken Naphtali, Petrov Kim G, Preugschat Frank, Schulte Christie, Shearer Barry G, Shearer Todd, Smalley Terrence L, Stewart Eugene L, Stuart J Darren, Ulrich John C
Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
J Med Chem. 2015 Apr 23;58(8):3548-71. doi: 10.1021/jm502009h. Epub 2015 Apr 10.
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.
合成了一系列噻唑并喹（嗪）啉酮，发现它们对CD38具有强效抑制活性。其中几种化合物还显示出良好的药代动力学性质，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，将化合物78c给予饮食诱导肥胖（DIO）的C57Bl6小鼠，在2小时时间点时，与对照动物相比，肝脏中的NAD升高了5倍以上，肌肉中的NAD升高了1.2倍以上。本文所述的化合物具有文献中迄今为止描述的任何小分子中最强效的CD38抑制活性。这些抑制剂应能更详细地评估通过抑制CD38提高NAD水平如何影响NAD缺乏状态下的生理功能。
