期刊论文

Yang, Wen-Chao

英文

Bioorganic & Medicinal Chemistry

0968-0896

2014

22

19

5194-5211

10.1016/j.bmc.2014.08.011

In summary, a series of hybrids of pyrazolone–quinazolone as human HPPD inhibitors were rationally designed through scaffold hopping, and subsequently optimized by combining computational simulations and experimental studies, leading to the discovery of several novel human HPPD inhibitors with excellent inhibitory potency. In particular, compounds 3h, characterized by a pyrazolone moiety linked to a substituted quinazolone, was identified as the most potent human HPPD inhibitor with Ki values

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4-Hydroxyphenylpyruvate dioxygenase (HPPD), converting 4-hydroxyphenylpyruvate acid to homogentisate, is an important target for treating type I tyrosinemia and alkaptonuria due to its significant role in tyrosine catabolism. However, only one commercial drug, NTBC, also known as nitisinone, has been available for clinical use so far. Herein, we have elucidated the structure-based design of a series of pyrazolone-quinazolone hybrids that are novel potent human HPPD inhibitors through the successful integration of various techniques including co...