ABSTRACT
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.
Subject(s)
ADAM17 Protein/antagonists & inhibitors , Hydantoins/chemistry , Hydantoins/chemical synthesis , Hydantoins/pharmacology , Pentanoic Acids/chemistry , Prodrugs/chemical synthesis , Prodrugs/pharmacology , ADAM17 Protein/metabolism , Administration, Oral , Animals , Area Under Curve , Dogs , Enzyme Activation/drug effects , Half-Life , Haplorhini , Humans , Hydantoins/administration & dosage , Hydantoins/pharmacokinetics , Pentanoic Acids/administration & dosage , Pentanoic Acids/pharmacokinetics , Prodrugs/administration & dosage , Prodrugs/pharmacokinetics , ROC Curve , Rats , Structure-Activity RelationshipABSTRACT
We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.
Subject(s)
ADAM17 Protein/antagonists & inhibitors , Hydantoins/chemistry , Protease Inhibitors/chemistry , ADAM17 Protein/metabolism , Animals , Area Under Curve , Dogs , Enzyme Activation/drug effects , Half-Life , Haplorhini , Humans , Hydantoins/chemical synthesis , Hydantoins/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , ROC Curve , Rats , Structure-Activity RelationshipABSTRACT
The installation of geminal substitution at the C5' position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5' position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species.
Subject(s)
Antiviral Agents/chemical synthesis , Carbohydrates/chemistry , Pyrimidines/chemistry , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Biological Availability , Dogs , Half-Life , Haplorhini , Hepacivirus/drug effects , Hepacivirus/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Virus Replication/drug effects , Animals , Antiviral Agents/pharmacokinetics , Dogs , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Pyrimidines/pharmacokinetics , Rats , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Thiazoles/pharmacologyABSTRACT
Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.
Subject(s)
Antiviral Agents/chemistry , Benzothiazoles/chemistry , Hepacivirus/drug effects , Pyrimidines/chemistry , Virus Replication/drug effects , Animals , Dogs , Haplorhini , Hepacivirus/physiology , Methylation , Rodentia , Species SpecificityABSTRACT
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Anti-Inflammatory Agents/chemistry , Arthritis, Rheumatoid/drug therapy , Protease Inhibitors/chemistry , ADAM Proteins/metabolism , ADAM17 Protein , Acetylene/analogs & derivatives , Acetylene/pharmacokinetics , Acetylene/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/therapeutic use , Dogs , Haplorhini , Humans , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/therapeutic use , RatsABSTRACT
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
