Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1),Journal of Medicinal Chemistry

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Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-07-24 00:00:00 , DOI: 10.1021/acs.jmedchem.5b00577
Shyh-Ming Yang ₁ , Adam Yasgar ₁ , Bettina Miller ₂ , Madhu Lal-Nag ₁ , Kyle Brimacombe ₁ , Xin Hu ₁ , Hongmao Sun ₁ , Amy Wang ₁ , Xin Xu ₁ , Kimloan Nguyen ₁ , Udo Oppermann _{3,

4} , Marc Ferrer ₁ , Vasilis Vasiliou _{2,

5} , Anton Simeonov ₁ , Ajit Jadhav ₁ , David J Maloney ₁

Affiliation

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 HSD17β4. Moreover, the pharmacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted.

中文翻译：

发现 NCT-501，一种基于茶碱的有效、选择性乙醛脱氢酶 1A1 (ALDH1A1) 抑制剂

醛脱氢酶（ALDH）代谢活性醛，在中枢神经系统、代谢紊乱和癌症等领域具有重要的生理和毒理学功能。 ALDH（例如 ALDH1A1）基因表达和催化活性的增加是许多恶性肿瘤和癌症干细胞中的重要生物标志物，这突出表明需要鉴定和开发小分子 ALDH 抑制剂。描述了一系列新的基于茶碱的类似物作为有效的 ALDH1A1 抑制剂。对定量高通量筛选 (qHTS) 活动中确定的命中进行优化，产生了具有改进效力和早期 ADME 特性的类似物。与 ALDH3A1、ALDH1B1 和 ALDH2 同工酶以及其他脱氢酶（例如 HPGD 和 HSD17β4）相比，该化学型对 ALDH1A1 表现出高度选择性抑制。此外，还重点介绍了所选类似物64 (NCT-501) 的药代动力学评估。

更新日期：2015-07-24

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