2. Academic Validation
  3. Discovery and extensive in vitro evaluations of NK-HDAC-1: a chiral histone deacetylase inhibitor as a promising lead

Discovery and extensive in vitro evaluations of NK-HDAC-1: a chiral histone deacetylase inhibitor as a promising lead

  • J Med Chem. 2012 Apr 12;55(7):3066-75. doi: 10.1021/jm201496g.
Jingli Hou 1,  Zhonghua Li,  Qinghong Fang,  Congran Feng,  Hanwen Zhang,  Weikang Guo,  Huihui Wang,  Guoxian Gu,  Yinping Tian,  Pi Liu,  Ruihua Liu,  Jianping Lin,  Yi-Kang Shi,  Zheng Yin,  Jie Shen,  Peng George Wang
Affiliations

Affiliation

  • 1 College of Pharmacy, Nankai University, Tianjin,China.
PMID: 22435669 DOI: 10.1021/jm201496g
Abstract

Herein, further SAR studies of lead compound NSC746457 (Shen, J.; Woodward, R.; Kedenburg, J. P.; Liu, X. W.; Chen, M.; Fang, L. Y.; Sun; D. X.; Wang. P. G. J. Med. Chem. 2008, 51, 7417-7427) were performed, including the replacement of the trans-styryl moiety with a 2-substituted benzo-hetero aromatic ring and the introduction of a substituent onto the central methylene carbon. A promising chiral lead, S-(E)-3-(1-(1-(benzo[d]oxazol-2-yl)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide (12, NK-HDAC-1), was discovered and showed about 1 order of magnitude more potency than SAHA in both enzymatic and cellular assays. For the in vitro safety tests, NK-HDAC-1 was far less toxic to nontransformed cells than tumor cells and showed no significant inhibition activity against CYP-3A4. The pharmaceutical properties (LogD, solubility, liver micrsomal stability (t1/2), plasma stability (t1/2), and apparent permeability) strongly suggested that NK-HDAC-1 might be superior to SAHA in bioavailability and in vivo half-life.

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