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Bioorg Med Chem Lett. 2015 Jan 1;25(1):75-82. Epub 2014 Nov 10.

Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.

Author information

1
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Abstract

Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (4–10 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency.

PMID:
25466195
DOI:
10.1016/j.bmcl.2014.11.008
[Indexed for MEDLINE]

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