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J Med Chem ; 63(23): 14740-14760, 2020 12 10.
Article in English | MEDLINE | ID: mdl-33226226

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 CF3Boc-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-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.


Subject(s)
Antiviral Agents/pharmacology , Peptides, Cyclic/pharmacology , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , CHO Cells , Cricetulus , Drug Discovery , Drug Stability , Hepacivirus/drug effects , Hepacivirus/enzymology , Microbial Sensitivity Tests , Microsomes, Liver/metabolism , Molecular Structure , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/metabolism , Peptides, Cyclic/pharmacokinetics , Rats , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/metabolism , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity Relationship
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