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Letter

Structure−Activity Study on a Novel Series of Macrocyclic Inhibitors of the Hepatitis C Virus NS3 Protease Leading to the Discovery of BILN 2061

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Montse Llinàs-Brunet,*^† Murray D. Bailey,^† Gordon Bolger,^‡ Christian Brochu,^† Anne-Marie Faucher,^† Jean Marie Ferland,^† Michel Garneau,^‡ Elise Ghiro,^† Vida Gorys,^† Chantal Grand-Maître,^† Ted Halmos,^† Nicole Lapeyre-Paquette,^‡ Francine Liard,^‡ Martin Poirier,^† Manon Rhéaume,^‡ Youla S. Tsantrizos,^† and Daniel Lamarre^‡

Departments of Chemistry and Biological Sciences, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Qubec H7S 2G5, Canada

J. Med. Chem., 2004, 47 (7), pp 1605–1608

DOI: 10.1021/jm0342414

Publication Date (Web): March 2, 2004

To whom correspondence should be addressed. Phone: 450-682-4640. Fax: 450-682-4189. E-mail: mllinas@ lav.boehringer-ingelheim.com.

†

Department of Chemistry.

‡

Department of Biological Sciences.

Abstract

From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure−activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.

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Published In Issue March 25, 2004
Received November 20, 2003

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Letter

Structure−Activity Study on a Novel Series of Macrocyclic Inhibitors of the Hepatitis C Virus NS3 Protease Leading to the Discovery of BILN 2061

Abstract

Tools

SciFinder Links

History

Recommend & Share

Related Content

Synthesis of BILN 2061, an HCV NS3 Protease Inhibitor with Proven Antiviral Effect in Humans

Efficient Large-Scale Synthesis of BILN 2061, a Potent HCV Protease Inhibitor, by a Convergent Approach Based on Ring-Closing Metathesis

A Systematic Approach to the Optimization of Substrate-Based Inhibitors of the Hepatitis C Virus NS3 Protease: Discovery of Potent and Specific Tripeptide Inhibitors

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