Discovery of 2-phenylthiazole-4-carboxylic acid, a novel and potent scaffold as xanthine oxidase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2019-02, Vol.29 (4), p.525-528
• Main Authors: Xu, Xue, Deng, Liming, Nie, Lu, Chen, Yueming, Liu, Yanzhi, Xie, Rongrong, Li, Zheng
• Format: Article
• Language: English
• Subjects: Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Febuxostat - pharmacology; Gout; Hyperuricemia; Hypouricemic effect; Thiazolidines - chemistry; Thiazolidines - pharmacology; Xanthine oxidase; Xanthine Oxidase - antagonists & inhibitors; XO inhibitor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.01.005

Aiming to exploring potent XO inhibitor with optimal heterocycle, we have identified a new 2-phenylthiazole-4-carboxylic acid scaffold by evaluating 5 heterocycle scaffolds unexplored in this field, exemplified by the potent and orally bioavailable XO inhibitor 8. [Display omitted] •2-Phenylthiazole-4-carboxylic acid was identified as a novel scaffold of xanthine oxidase inhibitors.•Compound 8 revealed equivalent XO inhibitory activities with the analog of Febuxostat (compound 7).•Compound 8 exhibited significantly hypouricemic effect in hyperuricemic mice. The xanthine oxidase (XO) plays an important role in producing uric acid, and therefore XO inhibitors are considered as one of the promising therapies for hyperuricemia and gout. We have previously reported a series of XO inhibitors with pyrazole scaffold to extend the chemical space of current XO inhibitors. Herein, we describe further structural optimization to explore the optimal heterocycle by replacing the thiazole ring of Febuxostat with 5 heterocycle scaffolds unexplored in this field. All of these efforts resulted in the identification of compound 8, a potent XO inhibitor (IC50 = 48.6 nM) with novel 2-phenylthiazole-4-carboxylic acid scaffold. Moreover, lead compound 8 exhibited hypouricemic effect in potassium oxonate-hypoxanthine-induced hyperuricemic mice. These results promote the understanding of ligand-receptor interaction and might help to design more promising XO inhibitors.