title: A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide.
abstract: Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC50= 9440 nM), a series of structurally related thiazole derivatives has been identified as a novel chemical class of potent and selective HCV NS5A inhibitors. The introduction of a carboxamide group between the thiazole and pyrrolidine ring (42) of compound 18 resulted in a dramatic increase in activity (EC50= 0.92 nM). However, 42 showed only moderate pharmacokinetic properties and limited oral bioavalability of 18.7% in rats. Further optimization of the substituents at the 4-position of the thiazole ring and pyrrolidine nitrogen of the lead compound 42 led to the identification of compound 57, a highly potent and selective NS5A inhibitor of HCV (EC50= 4.6 nM), with greater therapeutic index (CC50/EC50> 10000). Pharmacokinetic studies revealed that compound 57 had a superior oral exposure and desired bioavailability of 45% after oral administration in rats.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Iou-Jiun
authors.initials: IJ
authors.lastname: Kang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Sheng-Ju
authors.initials: SJ
authors.lastname: Hsu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Yang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Chung-Chi
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Tian
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Tsu-An
authors.initials: TA
authors.lastname: Hsu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Andrew
authors.initials: A
authors.lastname: Yueh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan ROC.
authors.forename: Jyh-Haur
authors.identifier: 0000-0003-4454-3018
authors.initials: JH
authors.lastname: Chern
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D016174:Hepacivirus / Q000187:drug effects*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011759:Pyrrolidines; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C000621652:(S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase