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

Autor:	Becherer JD; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Boros EE; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Carpenter TY; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Cowan DJ; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Deaton DN; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Haffner CD; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Jeune MR; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Kaldor IW; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Poole JC; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Preugschat F; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Rheault TR; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Schulte CA; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Shearer BG; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Shearer TW; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Shewchuk LM; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Smalley TL Jr; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Stewart EL; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Stuart JD; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States., Ulrich JC; GlaxoSmithKline Research and Development , 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2015 Sep 10; Vol. 58 (17), pp. 7021-56. Date of Electronic Publication: 2015 Aug 24.
DOI:	10.1021/acs.jmedchem.5b00992
Abstrakt:	Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, 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 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.
Databáze:	MEDLINE
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