ABSTRACT
Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Imidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazines/chemistry , Agammaglobulinaemia Tyrosine Kinase/metabolism , Animals , Arthritis, Experimental/drug therapy , Binding Sites , Bridged Bicyclo Compounds/chemistry , Crystallography, X-Ray , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Half-Life , Humans , Imidazoles/metabolism , Imidazoles/therapeutic use , Molecular Dynamics Simulation , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/therapeutic use , Pyrazines/metabolism , Pyrazines/therapeutic use , Rats , Rats, Wistar , Structure-Activity Relationship , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/metabolismABSTRACT
A series of novel tetracyclic core-containing HCV NS5A inhibitors has been discovered. Incorporation of tetrahydropyran-substituted amino acid moiety improved their potency and yielded HCV NS5A inhibitors with a minimum potency shift from the GT1a strain compared to other genotypes and mutants. Compounds 53 and 54 showed the best potency profile and had reasonable half-times in rat PK studies. However, further optimization of their oral bioavailability is still needed in order to advance them for further development. [BMCL ABSTRACT] ©2000 Elsevier Science Ltd. All rights reserved.
Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Genotype , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Half-Life , RatsABSTRACT
HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.
Subject(s)
Antiviral Agents/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Proline/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Dogs , Genotype , Half-Life , Haplorhini , Hepacivirus/drug effects , Hepacivirus/genetics , Hepacivirus/physiology , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Rats , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
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
8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Drug Discovery , Imidazoles/pharmacology , Morpholines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Arthritis, Rheumatoid/metabolism , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Models, Molecular , Molecular Structure , Morpholines/chemical synthesis , Morpholines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Transcriptional Regulator ERG/antagonists & inhibitors , Transcriptional Regulator ERG/metabolismABSTRACT
Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core.
Subject(s)
Indoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/pharmacology , Hepacivirus/drug effectsABSTRACT
Herein we describe our research efforts around the aryl and heteroaryl substitutions at the aminal carbon of the tetracyclic indole-based HCV NS5A inhibitor MK-8742. A series of potent NS5A inhibitors are described, such as compounds 45-47, 54, 56, and 65, which showed improved potency against clinically relevant and resistance associated HCV variants. The improved potency profiles of these compounds demonstrated an SAR that can improve the potency against GT2b, GT1a Y93H, and GT1a L31V altogether, which was unprecedented in our previous efforts in NS5A inhibition.
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 , Imidazoles/chemical synthesis , Imidazoles/chemistry , Male , Microbial Sensitivity Tests , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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
HCV NS5A inhibitors have demonstrated impressive in vitro virologic 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 (FDC) regimen for the treatment of HCV infection. Merck's effort in this area identified MK-4882 and MK-8325 as early development leads. Herein, we describe the discovery of potent macrocyclic NS5A inhibitors bearing the MK-8325 or MK-4882 core structure.
Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Macrocyclic Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Hepatitis C/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
As part of an ongoing effort in NS5A inhibition at Merck we now describe our efforts for introducing substitution around the tetracyclic indole core of MK-8742. Fluoro substitution on the core combined with the fluoro substitutions on the proline ring improved the potency against GT1a Y93H significantly. However, no improvement on GT2b potency was achieved. Limiting the fluoro substitution to C-1 of the tetracyclic indole core had a positive impact on the potency against the resistance associated variants, such as GT1a Y93H and GT2b, and the PK profile as well. Compounds, such as 62, with reduced potency shifts between wild type GT1a to GT2b, GT1a Y93H, and GT1a L31V were identified.
Subject(s)
Antiviral Agents/pharmacology , Benzofurans/pharmacology , Imidazoles/pharmacology , Indoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Benzofurans/chemistry , Benzofurans/pharmacokinetics , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Indoles/chemistry , Indoles/pharmacokinetics , Structure-Activity RelationshipABSTRACT
We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.
Subject(s)
Antiviral Agents/pharmacology , Benzofurans/pharmacology , Imidazoles/pharmacology , Indoles/chemistry , Proline/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Benzofurans/chemistry , Imidazoles/chemistry , Structure-Activity RelationshipABSTRACT
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 research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.
Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Hepatitis C/drug therapy , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Genotype , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Viral Nonstructural Proteins/genetics , Virus Replication/drug effectsABSTRACT
HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Hepacivirus/genetics , Proline/analogs & derivatives , Silanes/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Dose-Response Relationship, Drug , Genotype , Microbial Sensitivity Tests , Molecular Structure , Silanes/pharmacology , Structure-Activity Relationship , Viral Nonstructural Proteins/genetics , Virus Replication/drug effectsABSTRACT
The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.
Subject(s)
Amides/pharmacology , Drug Discovery , Ether-A-Go-Go Potassium Channels/metabolism , Heterocyclic Compounds/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Amides/administration & dosage , Amides/chemistry , Animals , Dose-Response Relationship, Drug , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/chemistry , Humans , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9µMh.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/pharmacology , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Cytochrome P-450 Enzyme System/metabolism , Guinea Pigs , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Rats , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 µM), highly selective, and safe in in vitro and in vivo assays.
Subject(s)
Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Indoles/chemistry , Quinolines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Crystallography, X-Ray , Dogs , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Haplorhini , Humans , Indoles/chemical synthesis , Indoles/pharmacokinetics , Indoles/pharmacology , Male , Molecular Dynamics Simulation , Protein Binding , Protein Structure, Tertiary , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Quinolines/pharmacology , Rats , Rats, Sprague-Dawley , Viral Nonstructural Proteins/metabolismABSTRACT
Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053µM, replicon EC(50)=4.8µM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039µM, replicon EC(50)=0.011µM) with >100-fold improved replicon activity.
Subject(s)
Antiviral Agents/pharmacology , Indoles/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
The structure-human CXCR3 binding affinity relationship of a series of pyridyl-piperazinyl-piperidine derivatives was explored. The optimization campaign highlighted the pronounced effect of 2'-piperazine substitution on CXCR3 receptor affinity. Analog 18j, harboring a 2'(S)-ethylpiperazine moiety, exhibited a human CXCR3 IC(50) of 0.2 nM.