Identification of 3,6-disubstituted dihydropyrones as inhibitors of human lactate dehydrogenase
2014; Elsevier BV; Volume: 24; Issue: 24 Linguagem: Inglês
10.1016/j.bmcl.2014.10.067
ISSN1464-3405
AutoresBenjamin P. Fauber, Peter S. Dragovich, Jinhua Chen, Laura Corson, Charles Z. Ding, Charles Eigenbrot, Sharada S. Labadie, Shiva Malek, David Peterson, Hans E. Purkey, Kirk Robarge, Steve Sideris, Mark Ultsch, BinQing Wei, Ivana Yen, Qin Yue, Aihe Zhou,
Tópico(s)Chemical Reaction Mechanisms
ResumoA series of 3,6-disubstituted dihydropyrones were identified as inhibitors of human lactate dehydrogenase (LDH)-A. Structure activity relationships were explored and a series of 6,6-spiro analogs led to improvements in LDHA potency (IC50 <350 nM). An X-ray crystal structure of an improved compound bound to human LDHA was obtained and it illustrated additional opportunities to enhance the potency of these compounds, resulting in the identification of 51 (IC50 = 30 nM).
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