Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38

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• 作者：J. David Becherer ; Eric E. Boros ; Tiffany Y. Carpenter ; David J. Cowan ; David N. Deaton ; Curt D. Haffner ; Michael R. Jeune ; Istvan W. Kaldor ; J. Chuck Poole ; Frank Preugschat ; Tara R. Rheault ; Christie A. Schulte ; Barry G. Shearer ; Todd W. Shearer ; Lisa M. Shewchuk ; Terrence L. Smalley ; Jr. ; Eugene L. Stewart ; J. Darren Stuart ; John C. Ulrich
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：58
• 期：17
• 页码：7021-7056
• 全文大小：1331K
• ISSN：1520-4804

文摘

Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure鈥揳ctivity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10鈥?00-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 NAD 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.