5IXS

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

Purkey, H.E., Robarge, K., Chen, J., Chen, Z., Corson, L.B., Ding, C.Z., DiPasquale, A.G., Dragovich, P.S., Eigenbrot, C., Evangelista, M., Fauber, B.P., Gao, Z., Ge, H., Hitz, A., Ho, Q., Labadie, S.S., Lai, K.W., Liu, W., Liu, Y., Li, C., Ma, S., Malek, S., O'Brien, T., Pang, J., Peterson, D., Salphati, L., Sideris, S., Ultsch, M., Wei, B., Yen, I., Yue, Q., Zhang, H., Zhou, A.

(2016) ACS Med Chem Lett 7: 896-901

• PubMed: 27774125 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1021/acsmedchemlett.6b00190
• Primary Citation of Related Structures:  
  5IXS, 5IXY


• PubMed 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 IC ₅₀ in a MiaPaca2 cell line. Optimization of the series led to 29 , a potent cell active molecule (MiaPaca2 IC ₅₀ = 0.67 μM) that also possessed good exposure when dosed orally to mice.

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Organizational Affiliation: 

Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.