Structure-activity relationships of 4-hydroxy-4-biaryl-proline acylsulfonamide tripeptides: A series of potent NS3 protease inhibitors for the treatment of hepatitis C virus

Hepatitis C: The Story of a Long Journey through First, Second, and Third Generation NS3/4A Peptidomimetic Inhibitors. What Did We Learn?

“…No benefits were seen by the following: Modification of the C-4 and C-7 positions of the isoquinoline ring; this work identified the C-4 methoxy and C-7 chloro as the best combinations leading to compounds with excellent inhibitory activity in the replicon assay, modest oral bioavailability and plasma AUC, but unfavorable hepatotropic distribution Replacing the P2 isoquinoline with the introduction of aryl groups (e.g., naphthyl, biphenyl) at the C-4 Pro; this attempt afforded compounds with low cell permeability or with unacceptable cardiovascular profile Modification of P1 (saturation of the terminal olefin and introduction of the difluoromethylene group at the P1 site as mimetic of the canonical cysteine thiol); compounds with inferior PK profile were obtained …”

“…Replacing the P2 isoquinoline with the introduction of aryl groups (e.g., naphthyl, biphenyl) at the C-4 Pro; this attempt afforded compounds with low cell permeability or with unacceptable cardiovascular profile …”

“…121 (2) Replacing the P2 isoquinoline with the introduction of aryl groups (e.g., naphthyl, biphenyl) at the C-4 Pro; this attempt afforded compounds with low cell permeability or with unacceptable cardiovascular profile. 122 (3) Modification of P1 (saturation of the terminal olefin and introduction of the difluoromethylene group at the P1 site as mimetic of the canonical cysteine thiol); 121 compounds with inferior PK profile were obtained. 123 (4) Modification of the P4 cap with urea and reverse carbamates in order to gain a tight binding thanks to the bidentate hydrogen-bonding interaction with the backbone carbonyl of Ala157.…”

Gold(I)-Initiated Cycloisomerization/Diels–Alder/Retro-Diels–Alder Cascade Strategy to Biaryls

“…Biaryls are important scaffolds in a wide range of natural products, pharmaceutically active molecules, chiral ligands, crown ethers, and liquid crystals . Due to the increasing demand for efficient strategies for constructing biaryl compounds, a number of methodologies have been developed, in which the transition-metal-catalyzed cross-coupling reactions were the predominant methods. ,, Moreover, a strategy to synthesize biaryls by the construction of one aryl ring via transition-metal-catalyzed [2+2+2] cycloaddition of alkynes or Diels–Alder cycloaddition/aromatization also drew considerable attention. ,, Also, some gold-catalyzed approaches to biaryls have been reported …”