Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Abstract

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1−P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1−P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF 3 Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1′ cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD 3 O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD 3 O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH 3 O prototype.

Discovery of Quinoxaline-Based P1–P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants

“…Compound 12 also showed improved inhibitory activity against the GT-3a protease and was comparable to GZR in GT-3a replicon assays (GT-3a EC 50 = 160 nM vs 65 nM for GZR). A recently reported cocrystal structure of the WT NS3/4A protease with BMS-986144 (PDB 7D5L), which contains the same P4 group, shows that the trifluoromethyl group makes favorable interactions with residues D168, R123, and V158 in the S4 pocket . The trifluoro tert -butyl group in 12 likely binds in a similar conformation, and the trifluoromethyl group, while avoiding direct contacts with A156, provides enhanced interactions with key variable residues in the S4 pocket, which are beneficial to activity against resistant variants and GT-3a.…”

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

“…Introduction of a carbon tethered between the P1 cyclopropyl moiety and the P3 residue backbone gave macrocyclic inhibitors more potent than asunaprevir (38) but with low bioavailability in rat, monkey, and dog. 126 (for more detail, see section 3.3.1.) Similarly to asunaprevir (38) and BMS-605339 (36), sovaprevir (ACH-1625, 39) (Figure 14), 127 developed by Achillion Pharmaceuticals, is a linear noncovalent inhibitor bearing the cyclopropyl acyl sulfonamide group at the P1 site.…”

Anno 2021: Which antivirals for the coming decade?

“…The macrocyclic scaffold structure shared by approved HCV NS3/4A protease inhibitors has been modified to modulate both potency and drug-like properties of the inhibitors as well as prevent resistance due to pre-existing resistance-associated substitutions (RASs) and/or baseline polymorphisms among diverse genotypes. 200 , 201 …”