1. Novel macrocyclic inhibitors of hepatitis C NS3/4A protease featuring a 2-amino-1,3-thiazole as a P4 carbamate replacement.
- Author
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Di Francesco ME, Dessole G, Nizi E, Pace P, Koch U, Fiore F, Pesci S, Di Muzio J, Monteagudo E, Rowley M, and Summa V
- Subjects
- Animals, Carrier Proteins chemistry, Catalytic Domain, Dogs, Humans, Intracellular Signaling Peptides and Proteins, Macrocyclic Compounds pharmacokinetics, Models, Molecular, Protease Inhibitors chemistry, Protease Inhibitors pharmacokinetics, Protease Inhibitors pharmacology, Rats, Viral Nonstructural Proteins chemistry, Viral Proteins chemistry, Carbamates chemistry, Carrier Proteins antagonists & inhibitors, Hepacivirus enzymology, Macrocyclic Compounds chemistry, Macrocyclic Compounds pharmacology, Thiazoles chemistry, Viral Nonstructural Proteins antagonists & inhibitors, Viral Proteins antagonists & inhibitors
- Abstract
Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and cellular activity. Among these, compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.
- Published
- 2009
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