Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591608 | Bioorganic & Medicinal Chemistry Letters | 2014 | 8 Pages |
Abstract
A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50 = 1.7 μM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50 = 0.18 μM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F = 45%).
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Authors
Peter S. Dragovich, Benjamin P. Fauber, Jason Boggs, Jinhua Chen, Laura B. Corson, Charles Z. Ding, Charles Eigenbrot, HongXiu Ge, Anthony M. Giannetti, Thomas Hunsaker, Sharada Labadie, Chiho Li, Yichin Liu, Yingchun Liu, Shuguang Ma, Shiva Malek,