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

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 ?M lactate IC50 in a MiaPaca2 cell line. Optimization of the series led to 29, a potent cell active molecule (MiaPaca2 IC50 = 0.67 ?M) that also possessed good exposure when dosed orally to mice.

SUBMITTER: Purkey HE

PROVIDER: S-EPMC5066143 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Purkey Hans E HE Robarge Kirk K Chen Jinhua J Chen Zhongguo Z Corson Laura B LB Ding Charles Z CZ DiPasquale Antonio G AG Dragovich Peter S PS Eigenbrot Charles C Evangelista Marie M Fauber Benjamin P BP Gao Zhenting Z Ge Hongxiu H Hitz Anna A Ho Qunh Q Labadie Sharada S SS Lai Kwong Wah KW Liu Wenfeng W Liu Yajing Y Li Chiho C Ma Shuguang S Malek Shiva S O'Brien Thomas T Pang Jodie J Peterson David D Salphati Laurent L Sideris Steve S Ultsch Mark M Wei BinQing B Yen Ivana I Yue Qin Q Zhang Huihui H Zhou Aihe A

ACS medicinal chemistry letters 20160826 10

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. ...[more]

PMID: 27774125

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