Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents

Nilsson, Magnus; Belfrage, Anna Karin; Lindstrom, Stefan; Wahling, Horst; Lindquist, Charlotta; Ayesa, Susana; Kahnberg, Pia; Pelcman, Mikael; Benkestock, Kurt; Agback, Tatiana; Vrang, Lotta; Terelius, Ylva; Wikstrom, Kristina; Hamelink, Elizabeth; Rydergard, Christina; Edlund, Michael; Eneroth, Anders; Raboisson, Pierre; Lin, Tse-I; de Kock, Herman; Wigerinck, Piet; Simmen, Kenneth; Samuelsson, Bertil; Rosenquist, Asa

doi:10.1016/j.bmcl.2010.05.029

Research article2010Peer reviewed

Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents

Nilsson, Magnus; Belfrage, Anna Karin; Lindstrom, Stefan; Wahling, Horst; Lindquist, Charlotta; Ayesa, Susana; Kahnberg, Pia; Pelcman, Mikael; Benkestock, Kurt; Agback, Tatiana; Vrang, Lotta; Terelius, Ylva; Wikstrom, Kristina; Hamelink, Elizabeth; Rydergard, Christina; Edlund, Michael; Eneroth, Anders; Raboisson, Pierre; Lin, Tse-I; de Kock, Herman;
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Abstract

Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. (C) 2010 Elsevier Ltd. All rights reserved.

Keywords

HCV; NS3/4A protease; Inhibitors; P2 substituent; Quinazoline; Replicon assay; In vitro; DMPK; In vivo PK

Published in

Bioorganic and Medicinal Chemistry Letters
2010, volume: 20, number: 14, pages: 4004-4011
Publisher: PERGAMON-ELSEVIER SCIENCE LTD

SLU Authors

Agback, Tatiana
- Medivir AB

UKÄ Subject classification

Medicinal Chemistry

Publication identifier

DOI: https://doi.org/10.1016/j.bmcl.2010.05.029

Permanent link to this page (URI)

https://res.slu.se/id/publ/99468