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
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