Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors

• Published in: Journal of medicinal chemistry Vol. 58; no. 8; pp. 3548 - 3571
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 23-04-2015
• Subjects: ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - metabolism; Animals; Cell Line; Dogs; Drug Discovery; Humans; Liver - drug effects; Liver - metabolism; Mice, Inbred C57BL; Molecular Docking Simulation; Muscles - drug effects; Muscles - metabolism; NAD - analysis; NAD - blood; NAD - metabolism; Obesity - drug therapy; Obesity - metabolism; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacokinetics; Quinolones - pharmacology; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacokinetics; Thiazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm502009h

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.