Literature DB >> 27774125

Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice.

Hans E Purkey1, Kirk Robarge1, Jinhua Chen2, Zhongguo Chen2, Laura B Corson1, Charles Z Ding2, Antonio G DiPasquale3, Peter S Dragovich1, Charles Eigenbrot1, Marie Evangelista1, Benjamin P Fauber1, Zhenting Gao2, Hongxiu Ge2, Anna Hitz1, Qunh Ho2, Sharada S Labadie1, Kwong Wah Lai2, Wenfeng Liu2, Yajing Liu2, Chiho Li2, Shuguang Ma1, Shiva Malek1, Thomas O'Brien1, Jodie Pang1, David Peterson1, Laurent Salphati1, Steve Sideris1, Mark Ultsch1, BinQing Wei1, Ivana Yen1, Qin Yue1, Huihui Zhang2, Aihe Zhou1.   

Abstract

A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 μM lactate IC50 in a MiaPaca2 cell line. Optimization of the series led to 29, a potent cell active molecule (MiaPaca2 IC50 = 0.67 μM) that also possessed good exposure when dosed orally to mice.

Entities:  

Keywords:  Lactate dehydrogenase; X-ray crystal structure; glycolysis; structure-based design; tumor metabolism

Year:  2016        PMID： 27774125      PMCID： PMC5066143          DOI： 10.1021/acsmedchemlett.6b00190

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


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