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Discovery and early clinical evaluation of BMS-605339, a potent and orally efficacious tripeptidic acylsulfonamide NS3 protease inhibitor for the treatment of hepatitis C virus infection.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2014 Mar 13; Vol. 57 (5), pp. 1708-29. Date of Electronic Publication: 2014 Feb 20. - Publication Year :
- 2014
-
Abstract
- The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
- Subjects :
- Animals
Crystallography, X-Ray
Dogs
Drug Evaluation, Preclinical
Humans
Isoquinolines chemistry
Models, Molecular
Protease Inhibitors chemistry
Sulfonamides chemistry
Antiviral Agents therapeutic use
Drug Discovery
Hepatitis C drug therapy
Isoquinolines therapeutic use
Protease Inhibitors therapeutic use
Sulfonamides therapeutic use
Viral Nonstructural Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 57
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24555570
- Full Text :
- https://doi.org/10.1021/jm401840s