國家衛生研究院 NHRI:Item 3990099045/11743

NHRI > Institute of Biotechnology and Pharmaceutical Research > Jyh-Haur Chern > Periodical Articles > Item 3990099045/11743

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/11743

Title:	A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus
Authors:	Yeh, TK;Kang, IJ;Hsu, TA;Lee, YC;Lee, CC;Hsu, SJ;Tian, YW;Yang, HY;Chen, CT;Chao, YS;Yueh, A;Chern, JH
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8, a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a-29a exhibited superior potency against GT1b with GT1b EC 50 values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1R,2S,1′R,2′S) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC 50 = 0.003 nM) than daclatasvir (GT1b EC 50 = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC 50 > 50 μM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection.
Date:	2019-04-01
Relation:	European Journal of Medicinal Chemistry. 2019 Apr 1;167:245-268.
Link to:	http://dx.doi.org/10.1016/j.ejmech.2019.02.016
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0223-5234&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000461728400018
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85061436939
Appears in Collections:	[Jyh-Haur Chern] Periodical Articles [Yueh Andrew Yueh] Periodical Articles [Yu-Sheng Chao(2002-2013)] Periodical Articles [Chiung-Tong Chen] Periodical Articles [John Tsu-An Hsu] Periodical Articles [Teng-Kuang Yeh] Periodical Articles

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