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A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2019 Apr 01; Vol. 167, pp. 245-268. Date of Electronic Publication: 2019 Feb 06. - Publication Year :
- 2019
-
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 <subscript>50</subscript> 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 <subscript>50</subscript> = 0.003 nM) than daclatasvir (GT1b EC <subscript>50</subscript> = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC <subscript>50</subscript> > 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.<br /> (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Amides chemistry
Animals
Biological Availability
Dogs
Humans
Rats
Sialyltransferases antagonists & inhibitors
Structure-Activity Relationship
Thiazoles chemistry
Thiazoles therapeutic use
Drug Discovery
Hepacivirus drug effects
Hepatitis C drug therapy
Thiazoles pharmacokinetics
Viral Nonstructural Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 167
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30772607
- Full Text :
- https://doi.org/10.1016/j.ejmech.2019.02.016