Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors

A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (Ki = 0.1 nM, EC50 = 4.5 nM) and selective (CC50 (Huh-7 cells) > 50 μM) inhibitor, displaying an excellent PK profile in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration.

Graphical abstractLead optimization performed on a series of proline-urea based macrocycles led to the identification of very potent and drug like HCV NS3/4A protease inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide