2. Academic Validation
  3. Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors

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

  • J Med Chem. 2015 Apr 23;58(8):3548-71. doi: 10.1021/jm502009h.
Curt D Haffner 1,  J David Becherer 1,  Eric E Boros 1,  Rodolfo Cadilla 1,  Tiffany Carpenter 1,  David Cowan 1,  David N Deaton 1,  Yu Guo 1,  Wallace Harrington 1,  Brad R Henke 1,  Michael R Jeune 1,  Istvan Kaldor 1,  Naphtali Milliken 1,  Kim G Petrov 1,  Frank Preugschat 1,  Christie Schulte 1,  Barry G Shearer 1,  Todd Shearer 1,  Terrence L Smalley Jr 1,  Eugene L Stewart 1,  J Darren Stuart 1,  John C Ulrich 1
Affiliations

Affiliation

  • 1 Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States.
PMID: 25828863 DOI: 10.1021/jm502009h
Abstract

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.

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