1. Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38.
- Author
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Becherer JD, Boros EE, Carpenter TY, Cowan DJ, Deaton DN, Haffner CD, Jeune MR, Kaldor IW, Poole JC, Preugschat F, Rheault TR, Schulte CA, Shearer BG, Shearer TW, Shewchuk LM, Smalley TL Jr, Stewart EL, Stuart JD, and Ulrich JC
- Subjects
- Amides chemical synthesis, Amides pharmacology, Aminoquinolines chemical synthesis, Aminoquinolines pharmacology, Animals, Biological Availability, Crystallography, X-Ray, Humans, Hydrolysis, Liver metabolism, Membranes, Artificial, Mice, Inbred C57BL, Models, Molecular, Muscle, Skeletal metabolism, Obesity metabolism, Permeability, Protein Conformation, Quinolines chemical synthesis, Quinolines pharmacology, Stereoisomerism, Structure-Activity Relationship, ADP-ribosyl Cyclase 1 antagonists & inhibitors, Amides chemistry, Aminoquinolines chemistry, NAD metabolism, Quinolines chemistry
- Abstract
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.
- Published
- 2015
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