ABSTRACT
[This corrects the article DOI: 10.1021/acsmedchemlett.8b00344.].
ABSTRACT
RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.
Subject(s)
Benzothiazoles/pharmacology , Phosphates/pharmacology , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors , Animals , Benzothiazoles/chemistry , Benzothiazoles/pharmacokinetics , Benzothiazoles/therapeutic use , Colitis/drug therapy , Dogs , Drug Discovery , Humans , Male , Mice , Molecular Docking Simulation , Phosphates/chemistry , Phosphates/pharmacokinetics , Phosphates/therapeutic use , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Quinazolines/therapeutic use , Rats, Sprague-Dawley , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Swine , Swine, MiniatureABSTRACT
RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 µM).
ABSTRACT
With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.
Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/enzymology , Macrocyclic Compounds/pharmacology , Quinazolinones/pharmacology , Sulfones/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Crystallography, X-Ray , Drug Discovery , Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacokinetics , Models, Molecular , Mutation , Quinazolinones/chemistry , Quinazolinones/pharmacokinetics , Rats , Sulfones/pharmacokinetics , Viral Nonstructural Proteins/geneticsABSTRACT
A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Binding Sites , Carrier Proteins/metabolism , Catalytic Domain , Cyclization , Genotype , Half-Life , Hepacivirus/genetics , Intracellular Signaling Peptides and Proteins , Kinetics , Liver/metabolism , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Molecular Docking Simulation , Mutation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Carrier Proteins/metabolism , Cyclization , Genotype , Half-Life , Hepacivirus/genetics , Intracellular Signaling Peptides and Proteins , Kinetics , Liver/metabolism , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Quinolines/chemistry , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
ABSTRACT
The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.
ABSTRACT
A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
Subject(s)
Hepacivirus/enzymology , Indoles/pharmacology , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Area Under Curve , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/metabolism , Cyclopropanes , Dogs , Drug Discovery , Drug Evaluation, Preclinical , Indoles/chemistry , Indoles/pharmacokinetics , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins , Isoindoles , Lactams, Macrocyclic , Leucine/analogs & derivatives , Liver/metabolism , Macaca mulatta , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacokinetics , Macrocyclic Compounds/pharmacology , Metabolic Clearance Rate , Models, Chemical , Molecular Structure , Pan troglodytes , Proline/analogs & derivatives , Rats , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Sulfonamides , Viral Nonstructural Proteins/metabolism , Viral Proteins/antagonists & inhibitors , Viral Proteins/metabolismABSTRACT
A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure-activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K(+) channel. Preferred compounds were subsequently evaluated for selectivity in an alpha(1)-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.
Subject(s)
Benzocycloheptenes/chemical synthesis , Neurotransmitter Agents/chemical synthesis , Pyridines/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Benzocycloheptenes/chemistry , Benzocycloheptenes/pharmacology , Cell Line , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Neurotransmitter Agents/chemistry , Neurotransmitter Agents/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Structure-Activity RelationshipSubject(s)
Antiviral Agents/chemistry , Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemistry , Quinolines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Hepacivirus/drug effects , Intracellular Signaling Peptides and Proteins , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.
Subject(s)
Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Serine Proteinase Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Macrocyclic Compounds/pharmacology , Models, Molecular , Rats , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistryABSTRACT
Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.