ABSTRACT
A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.
Subject(s)
Antiviral Agents/chemistry , Hepacivirus/metabolism , Indoles/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Area Under Curve , Genotype , Half-Life , Hepacivirus/drug effects , Hepacivirus/genetics , Indoles/metabolism , Indoles/pharmacology , ROC Curve , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein we describe our continued research efforts around the alkyl "Z group" modification of the tetracyclic indole-based NS5A inhibitor MK-8742, which led to the discovery of a series of potent NS5A inhibitors. Compounds 10 and 19 are of particular interests since they are as potent as our previous leads and have much improved rat pharmacokinetic profiles.
Subject(s)
Antiviral Agents/pharmacology , Benzofurans/pharmacology , Hepacivirus/drug effects , Imidazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Benzofurans/chemical synthesis , Benzofurans/chemistry , Dose-Response Relationship, Drug , Hepatitis C/drug therapy , Imidazoles/chemical synthesis , Imidazoles/chemistry , Male , Microbial Sensitivity Tests , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
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
TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Amides/pharmacology , Enzyme Inhibitors/pharmacology , Pyrrolidines/chemistry , Tartrates/chemistry , ADAM17 Protein , Amides/chemical synthesis , Amides/chemistry , Animals , Biological Availability , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Molecular Structure , RatsABSTRACT
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 report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of compounds (I), which are potent CB(2) receptor ligands with excellent selectivity over the CB(1) receptor. This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and C-rings. Compound 42 has excellent CB(2) potency, selectivity and rat exposure.
Subject(s)
Receptor, Cannabinoid, CB2/drug effects , Sulfones/chemistry , Sulfones/pharmacology , Animals , Ligands , Rats , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship , Sulfones/metabolismABSTRACT
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.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , ADAM17 Protein , Animals , Rats , Structure-Activity RelationshipABSTRACT
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Protease Inhibitors/chemistry , Tartrates/chemistry , ADAM Proteins/metabolism , ADAM17 Protein , Animals , Binding Sites , Computer Simulation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Tartrates/chemical synthesis , Tartrates/pharmacokineticsABSTRACT
We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Hydantoins/pharmacology , ADAM17 Protein , Enzyme Inhibitors/chemistry , Hydantoins/chemistry , Hydrogen Bonding , Models, Molecular , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.
Subject(s)
Receptor, Cannabinoid, CB2/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfones/chemistry , Sulfones/chemical synthesis , Animals , Calcium Channels/metabolism , Cytochrome P-450 Enzyme System , Drug Inverse Agonism , Humans , Piperidines/chemistry , Rats , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfones/pharmacokineticsABSTRACT
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.
Subject(s)
Chemistry, Pharmaceutical/methods , Receptor, Cannabinoid, CB2/chemistry , Sulfones/chemistry , Animals , Drug Design , Drug Evaluation, Preclinical , Kinetics , Ligands , Models, Chemical , Protein Binding , Rats , Receptors, Drug , Sodium/chemistry , Structure-Activity RelationshipABSTRACT
We recently reported that compound 1 is a potent inhibitor of the CB2 receptor with high selectivity over CB1. This paper describes the SAR development for this class of compounds. Variation of the substitution pattern on the aromatic rings, as well as the groups linking them together, led to sub-nanomolar inhibitors of the CB2 receptor, with high selectivity over CB1.