Macrocyclic inhibitors of HCV NS3 protease

Abstract

Macrocyclization has proved to be an effective tool for depeptidization of peptidic inhibitors with improved binding and pharmacokinetic properties.

Identification of ligands that target the HCV-E2 binding site on CD81

“…During HCV replication, the post-translational processing and cleavage of the virus polyprotein produces ten structural and non-structural proteins. The crystal structures that have been determined for a number of these proteins are being used to facilitate both drug and vaccine development [2][3][4][5][6][7][8][9].…”

Induced‐Fit Binding of the Macrocyclic Noncovalent Inhibitor TMC435 to its HCV NS3/NS4A Protease Target

“…NS3/NS4A protease activity is essential to the HCV life cycle 2–4. Small‐molecule inhibitors of NS3/NS4A protease have been widely explored5–7 and are typically grouped into two classes: linear peptidomimetics with a ketoamide functionality that reacts with the catalytic Ser to form a reversible enzyme–inhibitor adduct, and noncovalent peptidomimetics containing a macrocycle8 (e.g. Figure 1); macrocyclic ketoamide inhibitors have also been reported 7.…”

The Synthesis of Macrocycles for Drug Discovery

“…Specifically, this strategy has been successfully applied to macrocyclic BACE inhibitors (47), 62,106-113 calpain inhibitors (48), 114,115 checkpoint kinase 1 (Chk1) inhibitors (49), [116][117][118] G-quadruplex stabilizing agents, 119 Grb2 SH2 domain inhibitors (50), 39,120-122 non-natural product inspired pan-HDAC inhibitors (51), 123 HIV inhibitors, [124][125][126][127] Hsp90 inhibitors (52), 128,129 insulin-regulated aminopeptidase (IRAP) inhibitors, 130 However, the most significant impact of this approach has been in the discovery and development of the plethora of macrocyclic HCV NS3/4A protease inhibitors, which relied almost exclusively on RCM to assemble the macrocyclic framework. [141][142][143] This includes several compounds that have progressed to advanced clinical evaluation, such as ITMN-191 (danoprevir, 55, Figure 11.7, site of cyclization indicated along with the catalyst employed using the designations in Figure 11.5), 144 Another series of clinical stage compounds prepared utilizing RCM are the multi-kinase inhibitors SB1317 (TG02, 62, Figure 11.8), an inhibitor of CDKs, Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3) for the treatment of cancers, including multiple myeloma and acute leukaemia, 154,155 SB1518 (pacritnib, 63), a JAK2, FLT3 and tyrosine kinase 2 (TYK2) inhibitor for the treatment of myelofibrosis and lymphoma, 156,157 and SB1578 (64), an inhibitor of JAK2, FLT3 and colony stimulating factor-1 receptor kinase (c-Fms) for the treatment of rheumatoid arthritis. 158 As is evident from the structures, these all originated from the same diaminopyridine-based core template.…”