Discovery of 4-amino-8-quinoline carboxamides as novel, submicromolar inhibitors of NAD-hydrolyzing enzyme CD38
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.
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Thiazoloquin(az)olin(on)es, including 78c, are potent inhibitors of CD38.
“thiazoloquin(az)olin(on)es, such as the small molecule 78c, have been identified as potent CD38 inhibitors”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Becherer et al., 2015
A single oral dose of 78c raises tissue NAD+ in the liver of young mice on a high-fat diet.
“Previous studies have shown that a single oral dose of 78c increases tissue NAD+ levels in the liver of young mice fed a high fat diet”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Becherer et al., 2015
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- Authors
- Becherer, J. D., Boros, E. E., Carpenter, T. Y., Cowan, D. J., Deaton, D. N., Haffner, C. D., Jeune, M. R., Kaldor, I. W., Poole, J. C., Preugschat, F., Rheault, T. R., Schulte, C. A., Shearer, B. G., Shearer, T. W., Shewchuk, L. M., Smalley, T. L., Stewart, E. L., Stuart, J. D., & Ulrich, J. C.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Deaton, David N.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-08-24
- Volume
- 58
- Issue
- 17
- Pages
- 7021-7056
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2225399376
- Cited by
- 55
- References
- 23
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 2 · 2020: 7 · 2019: 8 · 2018: 7 · 2017: 3 · 2016: 5 · 2015: 1
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Keywords
- CD38 inhibitors, NAD+ hydrolysis, structure-activity relationship, pharmacokinetics, oral bioavailability, diet-induced obesity, enzyme inhibitors
- MeSH terms
- Amides, Aminoquinolines, Animals, Biological Availability, Humans, Hydrolysis, Liver, Membranes, Artificial, Mice, Inbred C57BL, Models, Molecular, NAD, Obesity, Permeability, Protein Conformation, Quinolines, Stereoisomerism, Structure-Activity Relationship, Crystallography, X-Ray, Muscle, Skeletal, ADP-ribosyl Cyclase 1
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