Discovery of novel potent and selective dipeptide hepatitis C virus NS3/4A serine protease inhibitors

Bioorganic & Medicinal Chemistry Letters
Pierre RaboissonKenneth Simmen

Abstract

Starting from the previously reported HCV NS3/4A protease inhibitor BILN 2061, we have used a fast-follower approach to identify a novel series of HCV NS3/4A protease inhibitors in which (i) the P3 amino moiety and its capping group have been truncated, (ii) a sulfonamide is introduced in the P1 cyclopropyl amino acid, (iii) the position 8 of the quinoline is substituted with a methyl or halo group, and (iv) the ring size of the macrocycle has been reduced to 14 atoms. SAR analysis performed with a limited set of compounds led to the identification of N-{17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo [13.3.0.0 [Bartenschlager, R.; Lohmann, V. J. Gen. Virol. 2000, 81, 1631; Vincent Soriano, Antonio Madejon, Eugenia Vispo, Pablo Labarga, Javier Garcia-Samaniego, Luz Martin-Carbonero, Julie Sheldon, Marcelle Bottecchia, Paula Tuma, Pablo Barreiro Expert Opin. Emerg. Drugs, 2008, 13, 1-19]]octadec-7-ene-4-carbonyl}(1-methylcyclopropyl)(1-methylcyclopropyl)sulfonamide 19l an extremely potent (K(i)=0.20 nM, EC(50)=3.7 nM), selective, and orally bioavailable dipeptide NS3/4A protease inhibitor, which has features attractive for further preclinical development.

References

Jun 24, 1998·Biochemistry·C SteinkühlerR De Francesco
Aug 17, 2002·Protein Expression and Purification·Anton PoliakovU Helena Danielson
Oct 31, 2002·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Michael W Fried
Jan 31, 2004·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·François PeninJean-Michel Pawlotsky
Feb 10, 2004·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jean-Michel Pawlotsky, John G McHutchison
Sep 8, 2005·Expert Opinion on Investigational Drugs·Nathalie Goudreau, Montse Llinàs-Brunet
Mar 7, 2008·Expert Opinion on Emerging Drugs·Vincent SorianoPablo Barreiro

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Citations

Jan 23, 2009·PLoS Neglected Tropical Diseases·Dariusz EkonomiukDanzhi Huang
Mar 18, 2016·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Gamal Eldeen EsmatSahar H Ahmed
Jan 23, 2014·Journal of Medicinal Chemistry·Åsa RosenquistMaria Beumont-Mauviel

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