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  • Nilsson, Magnus, et al. (författare)
  • Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease : exploration of P2 quinazoline substituents.
  • Annan publikation (övrigt vetenskapligt/konstnärligt)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 of macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution for the P2 cyclopentane dicarboxylic acid series improved on the stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. properties were assessed in rat on selected compounds. Excellent exposure and liver–to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. In vivo pharmacokinetic properties were assessed in rat on selected compounds. Excellent exposure and liver–to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series.
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