ABSTRACT
An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.
ABSTRACT
In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4-proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/enzymology , Proline/analogs & derivatives , Protease Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , Drug Design , Half-Life , Hepacivirus/physiology , Molecular Docking Simulation , Proline/chemical synthesis , Proline/pharmacokinetics , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/enzymology , Oligopeptides/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Thiazoles/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Aminoisobutyric Acids , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Hepacivirus/genetics , Humans , Leucine/analogs & derivatives , Male , Microsomes, Liver/metabolism , Oligopeptides/pharmacokinetics , Oligopeptides/pharmacology , Proline/analogs & derivatives , Quinolines , Rats , Rats, Sprague-Dawley , Replicon/drug effects , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacologyABSTRACT
The synthesis and self-association of protected oxymethylene-bridged UA analogues are described.
