TY - JOUR
T1 - Discovery and extensive in vitro evaluations of NK-HDAC-1
T2 - A chiral histone deacetylase inhibitor as a promising lead
AU - Hou, Jingli
AU - Li, Zhonghua
AU - Fang, Qinghong
AU - Feng, Congran
AU - Zhang, Hanwen
AU - Guo, Weikang
AU - Wang, Huihui
AU - Gu, Guoxian
AU - Tian, Yinping
AU - Liu, Pi
AU - Liu, Ruihua
AU - Lin, Jianping
AU - Shi, Yi Kang
AU - Yin, Zheng
AU - Shen, Jie
AU - Wang, Peng George
PY - 2012/4/12
Y1 - 2012/4/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84859789575&partnerID=8YFLogxK
U2 - 10.1021/jm201496g
DO - 10.1021/jm201496g
M3 - Article
C2 - 22435669
AN - SCOPUS:84859789575
SN - 0022-2623
VL - 55
SP - 3066
EP - 3075
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -