Discovery of novel potent and selective dipeptide hepatitis C virus NS3/4A serine protease inhibitors
| Autor: | Frederic Delouvroy, Dominique Louis Nestor Ghislain Surleraux, Herman de Kock, Oliver Lenz, David McGowan, Pierre Raboisson, Magnus Nilsson, Åsa Rosenquist, Wim Van De Vreken, Hu Lili, Piet Wigerinck, Tse-I Lin, Bertil Samuelsson, Abdellah Tahri, Vendeville Sandrine Marie Hele, Kenneth Simmen |
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| Rok vydání: | 2008 |
| Předmět: |
Macrocyclic Compounds
Serine Proteinase Inhibitors Stereochemistry medicine.medical_treatment Clinical Biochemistry Administration Oral Pharmaceutical Science Viral Nonstructural Proteins Antiviral Agents Biochemistry Structure-Activity Relationship chemistry.chemical_compound Dogs Drug Discovery Peptide synthesis medicine Animals Combinatorial Chemistry Techniques Protease inhibitor (pharmacology) Molecular Biology chemistry.chemical_classification Sulfonamides NS3 Protease Dipeptide Molecular Structure biology Organic Chemistry Cyclic peptide Rats Sulfonamide Thiazoles Liver chemistry Enzyme inhibitor Quinolines biology.protein Molecular Medicine Carbamates |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 18:5095-5100 |
| ISSN: | 0960-894X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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