Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 15, Pages 5967-5978Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00577
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Funding
- National Center for Advancing Translational Sciences
- Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [U54MH084681]
- National Institutes of Health [AA022057, AA021724]
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Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The optimization of hits identified from a quantitative high throughput screening (qHTS) campaign led to analogs with improved potency and early ADME properties. This chemotype exhibits highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1, and ALDH2 isozymes as well as other dehydrogenases such as HPGD and HSD17 beta 4. Moreover, the pharrnacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted.
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