Discovery, synthesis, and biological evaluation of thiazoloquin(az)olin(on)es as potent CD38 inhibitors
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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4-Aminoquinoline derivatives, including compound 78c, inhibit CD38.
“Additionally, several derivatives of 4-aminoquinoline, including the compound 78c, inhibit CD38 and boost NAD+ levels in mouse muscle, liver and heart230.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [230]
Compound 78c raises NAD+ levels in mouse muscle, liver and heart.
“Additionally, several derivatives of 4-aminoquinoline, including the compound 78c, inhibit CD38 and boost NAD+ levels in mouse muscle, liver and heart230.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [230]
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 Haffner 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 Haffner et al., 2015
Cites
Mammalian Sirtuins: Biological Insights and Disease Relevance
Haigis, M. C., & Sinclair, D. A. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092250 · Cited by 2,085 · see citing works
Poly(ADP-ribose): novel functions for an old molecule
Schreiber, V., Dantzer, F., Amé, J., & de MURCIA, G. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1963 · Cited by 1,917 · see citing works
The Sir2 Family of Protein Deacetylases
Blander, G., & Guarente, L. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073651 · Cited by 1,496 · see citing works
Ying, W. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1672 · Cited by 1,494 · see citing works
The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways
Houtkooper, R. H., Cantó, C., Wanders, R. J., & Auwerx, J. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0026 · Cited by 899 · see citing works
Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology
Malavasi, F., Deaglio, S., Funaro, A., Ferrero, E., Horenstein, A. L., Ortolan, E., Vaisitti, T., & Aydin, S. (2008) · Physiological Reviews · doi:10.1152/physrev.00035.2007 · Cited by 862 · see citing works
The riboswitch control of bacterial metabolism
Nudler, E. (2003) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.11.004 · Cited by 574 · see citing works
Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue
Massudi, H., Grant, R., Braidy, N., Guest, J., Farnsworth, B., & Guillemin, G. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042357 · Cited by 545 · see citing works
The new life of a centenarian: signalling functions of NAD(P)
Berger, F. (2004) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2004.01.007 · Cited by 489 · see citing works
Targeting Sirtuin 1 to Improve Metabolism: All You Need Is NAD+?
Cantó, C., & Auwerx, J. (2012) · Pharmacological Reviews · doi:10.1124/pr.110.003905 · Cited by 433 · see citing works
Regulation of intracellular levels of NAD: A novel role for CD38
Aksoy, P., White, T. A., Thompson, M., & Chini, E. N. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.05.042 · Cited by 353 · see citing works
Chini, E. N. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209787185788 · Cited by 193 · see citing works
NAD <sup>+</sup> metabolism: A therapeutic target for age-related metabolic disease
Mouchiroud, L., Houtkooper, R. H., & Auwerx, J. (2013) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2013.789479 · Cited by 193 · see citing works
NAD metabolism and sirtuins: Metabolic regulation of protein deacetylation in stress and toxicity
Yang, T., & Sauve, A. A. (2006) · The AAPS Journal · doi:10.1208/aapsj080472 · Cited by 170 · see citing works
Practical Application of Computer-Aided Drug Design
Charifson, P. S. (1997) · Medical Entomology and Zoology · Cited by 162 · see citing works
Exploring the therapeutic space around NAD+
Houtkooper, R. H., & Auwerx, J. H. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201207019 · Cited by 109 · see citing works
Flavonoids as inhibitors of human CD38
Kellenberger, E., Kuhn, I., Schuber, F. J., & Muller‐Steffner, H. (2011) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2011.05.022 · Cited by 104 · see citing works
Koch‐Nolte, F., Haag, F., Guse, A. H., Lund, F. E., & Ziegler, M. (2009) · Science Signaling · doi:10.1126/scisignal.257mr1 · Cited by 82 · see citing works
Dickinson, E. (2006) · The FASEB Journal · doi:10.1096/fj.07-0101 · Cited by 71 · see citing works
Aging signaling pathways and circadian clock-dependent metabolic derangements
Tevy, M. F., Giebultowicz, J. M., Pincus, Z., Mazzoccoli, G., & Vinciguerra, M. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.12.002 · Cited by 66 · see citing works
The molecular "Jekyll and Hyde" duality of PARP1 in cell death and cell survival
Paul, O. H. (2009) · Frontiers in bioscience · doi:10.2741/3232 · Cited by 53 · see citing works
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Masuda, N., & Nakamura, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044169 · Cited by 45 · see citing works
Cai, G., Cole, S. A., FREELAND-GRAVES, J. H., MacCluer, J. W., Blangero, J., & Comuzzie, A. G. (2004) · Human Biology · doi:10.1353/hub.2005.0001 · Cited by 41 · see citing works
Vitamin B3, the nicotinamide adenine dinucleotides and aging
Xu, P., & Sauve, A. A. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2010.03.006 · Cited by 38 · see citing works
Design, synthesis and biological characterization of novel inhibitors of CD38
Dong, M., Si, Y.-Q., Sun, S.-Y., Pu, X., Yang, Z.-J., Zhang, L., Zhang, L., Leung, F. P., Lam, C. M. C., Kwong, A. K., et al. (2011) · Organic & Biomolecular Chemistry · doi:10.1039/c0ob00768d · Cited by 37 · see citing works
Primas, N., Bouillon, A., Lancelot, J., El‐Kashef, H., & Rault, S. (2009) · Tetrahedron · doi:10.1016/j.tet.2009.05.013 · Cited by 34 · see citing works
Design, Synthesis and SAR Studies of NAD Analogues as Potent Inhibitors towards CD38 NADase
Wang, S., Zhu, W., Wang, X., Li, J., Zhang, K., Zhang, L., Zhao, Y. J., Lee, H., & Zhang, L. (2014) · Molecules · doi:10.3390/molecules191015754 · Cited by 32 · see citing works
Catalysis-Based Inhibitors of the Calcium Signaling Function of CD38
Kwong, A. K., Chen, Z., Zhang, H., Leung, F. P., Lam, C. M. C., Ting, K. Y., Zhang, L., Hao, Q., Zhang, L., & Lee, H. C. (2011) · Biochemistry · doi:10.1021/bi201509f · Cited by 32 · see citing works
Preugschat, F., Tomberlin, G. H., & Porter, D. J. T. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.09.005 · Cited by 30 · see citing works
Self-citationA pre-steady state and steady state kinetic analysis of the N-ribosyl hydrolase activity of hCD157
Preugschat, F., Carter, L. H., Boros, E. E., Porter, D. J. T., Stewart, E. L., & Shewchuk, L. M. (2014) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.09.008 · Cited by 29 · see citing works
Self-citationDesign, Synthesis and Biological Evaluation of Noncovalent Inhibitors of Human CD38 NADase
Zhou, Y., Ting, K. Y., Lam, C. M. C., Kwong, A. K., Xia, J., Jin, H., Liu, Z., Zhang, L., Lee, H. C., & Zhang, L. (2012) · ChemMedChem · doi:10.1002/cmdc.201100487 · Cited by 23 · see citing works
Growth Prior to Thermogenesis for a Quick Fledging of Adélie Penguin Chicks (Pygoscelis adeliae)
Dégletagne, C., Roussel, D., Rouanet, J. L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074154 · Cited by 21 · see citing works
Swarbrick, J. M., Graeff, R. M., Zhang, H., THOMAS, M. P., Hao, Q., & Potter, B. V. L. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501037u · Cited by 19 · see citing works
Zhang, L., Kwong, A. K., Yang, Z., et al. (2011) · Heterocycles · doi:10.3987/com-11-12361 · Cited by 11 · see citing works
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Cited by
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Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648 · see citing works
NAD+ metabolism and its roles in cellular processes during ageing
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00313-x · Cited by 1,617 · see citing works
Camacho-Pereira, J., Tarragó, M. G., Chini, C. C. S., Nin, V., Escande, C., Warner, G. M., Puranik, A. S., Schoon, R. A., Reid, J. M., Galina, A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.006 · Cited by 901 · see citing works
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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., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00992 · Cited by 55 · see citing works
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- Authors
- Haffner, C. D., Becherer, J. D., Boros, E. E., Cadilla, R., Carpenter, T., Cowan, D., Deaton, D. N., Guo, Y., Harrington, W., Henke, B. R., Jeune, M. R., Kaldor, I., Milliken, N., Petrov, K. G., Preugschat, F., Schulte, C., Shearer, B. G., Shearer, T., Smalley, T. L., Stewart, E. L., Stuart, J. D., & Ulrich, J. C.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Research and Development, GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709, United States
- Corresponding author
- Haffner, Curt D.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-04-10
- Volume
- 58
- Issue
- 8
- Pages
- 3548-3571
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2333241266
- Cited by
- 137
- References
- 34
- Citations by year
- 2026: 17 · 2025: 12 · 2024: 6 · 2023: 9 · 2022: 13 · 2021: 12 · 2020: 18 · 2019: 10 · 2018: 11 · 2017: 10 · 2016: 14 · 2015: 5
- FWCI
- 6.82
- 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
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- CD38 inhibitors, NAD+ depletion, pharmacokinetics, diet-induced obesity, small molecule inhibitors, NAD+ metabolism
- MeSH terms
- Animals, Cell Line, Dogs, Humans, Liver, Mice, Inbred C57BL, Muscles, NAD, Obesity, Thiazoles, Quinolones, ADP-ribosyl Cyclase 1, Drug Discovery, Molecular Docking Simulation
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