ABSTRACT
A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.
Subject(s)
Calcium Channel Blockers/chemistry , Calcium Channel Blockers/therapeutic use , Calcium Channels, N-Type/metabolism , Neuralgia/drug therapy , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Analgesics/chemistry , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Calcium/metabolism , Calcium Channel Blockers/pharmacology , Drug Discovery , HEK293 Cells , Humans , Male , Neuralgia/metabolism , Patch-Clamp Techniques , Pyrans/chemistry , Pyrans/pharmacology , Pyrans/therapeutic use , Pyrazoles/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Hypoglycemic Agents/pharmacology , Pyrroles/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Dose-Response Relationship, Drug , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Mice , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of 2-thio-5-thiomethyl substituted imidazoles was discovered to be potent TGR5 agonists that possessed glucose-lowering effects while inhibiting gall bladder emptying in mice.
Subject(s)
Diabetes Mellitus/drug therapy , Gallbladder Emptying/drug effects , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Imidazoles/chemistry , Imidazoles/therapeutic use , Receptors, G-Protein-Coupled/agonists , Animals , Blood Glucose/analysis , Blood Glucose/metabolism , Cell Line , Diabetes Mellitus/blood , Diabetes Mellitus/metabolism , Diabetes Mellitus/physiopathology , Humans , Hypoglycemic Agents/pharmacology , Imidazoles/pharmacology , Methylation , Mice , Mice, Inbred C57BL , Receptors, G-Protein-Coupled/metabolismABSTRACT
A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.
Subject(s)
Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Biological Availability , Blood Glucose/analysis , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Drug Design , HEK293 Cells , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacokinetics , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/therapeutic use , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Mice, Inbred C57BL , Phenylpropionates/pharmacokinetics , Phenylpropionates/therapeutic use , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
SAR study of 5-aminooctahydrocyclopentapyrrole-3a-carboxamide scaffold led to identification of several CCR2 antagonists with potent activity in both binding and functional assays. Their cardiovascular safety and pharmacokinetic properties were also evaluated.
Subject(s)
Cyclopentanes/pharmacology , Drug Discovery , Pyrroles/pharmacology , Receptors, CCR2/antagonists & inhibitors , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Conformation , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
The discovery of a novel series of cyclopenta[b]furans as CCR2 inhibitors is discussed. This series has excellent CCR2 potency and PK characteristics, and good cardiovascular safety.
Subject(s)
Furans/chemistry , Furans/pharmacology , Receptors, CCR2/antagonists & inhibitors , Cell Line , Chemokine CCL2/immunology , Humans , Receptors, CCR2/immunologyABSTRACT
A novel series of substituted tetrahydropyrrolo[3,4-c]pyrazoles were investigated as blockers of the N-type calcium channel (Cav2.2 channels), a chronic pain target.
Subject(s)
Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/metabolism , Pyrazoles/chemistry , Pyrazoles/pharmacology , Animals , Calcium Channel Blockers/metabolism , Chronic Pain/drug therapy , Humans , Microsomes, Liver/metabolism , Pyrazoles/metabolism , Rats , Structure-Activity RelationshipABSTRACT
A novel series of substituted 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles were investigated as N-type calcium channel blockers (Cav2.2 channels), a chronic pain target. One compound was active in vivo in the rat CFA pain model.
Subject(s)
Analgesics/chemistry , Analgesics/pharmacology , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/metabolism , Pyrazoles/chemistry , Pyrazoles/pharmacology , Analgesics/metabolism , Analgesics/pharmacokinetics , Animals , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/pharmacokinetics , Microsomes, Liver/metabolism , Pain/drug therapy , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , RatsABSTRACT
The inflammatory response associated with the activation of C-C chemokine receptor CCR2 via it's interaction with the monocyte chemoattractant protein-1 (MCP-1, CCL2) has been implicated in many disease states, including rheumatoid arthritis, multiple sclerosis, atherosclerosis, asthma and neuropathic pain. Small molecule antagonists of CCR2 have been efficacious in animal models of inflammatory disease, and have been advanced into clinical development. The necessity to attenuate hERG binding appears to be a common theme for many of the CCR2 antagonist scaffolds appearing in the literature, presumably due the basic hydrophobic motif present in all of these molecules. Following the discovery of a novel cyclohexyl azetidinylamide CCR2 antagonist scaffold, replacement of the amide bond with heterocyclic rings was explored as a strategy for reducing hERG binding and improving pharmacokinetic properties.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Azetidines/chemistry , Azetidines/pharmacology , Receptors, CCR2/antagonists & inhibitors , Animals , Humans , MiceABSTRACT
Novel CCR2 antagonists with a novel 2-aminooctahydrocyclopentalene-3a-carboxamide scaffold were designed. SAR studies led to a series of potent compounds. For example, compound 51 had a good PK profile in both dog and monkey, and exhibited excellent efficacy when dosed orally in an inflammation model in hCCR2 KI mice. In addition, an asymmetric synthesis to the core structures was developed.
Subject(s)
Amides/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Cyclopentanes/chemistry , Pyridines/chemistry , Receptors, CCR2/antagonists & inhibitors , Administration, Oral , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Disease Models, Animal , Dogs , Half-Life , Haplorhini , Humans , Inflammation/drug therapy , Mice , Mice, Knockout , Protein Binding , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Receptors, CCR2/genetics , Receptors, CCR2/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.
Subject(s)
Analgesics/chemical synthesis , Calcium Channel Blockers/chemical synthesis , Calcium Channels, N-Type/metabolism , Chronic Pain/drug therapy , Neuralgia/drug therapy , Piperidines/chemical synthesis , Pyrazoles/chemical synthesis , Analgesics/therapeutic use , Animals , Calcium Channel Blockers/therapeutic use , Cell Line , Chronic Pain/metabolism , High-Throughput Screening Assays , Humans , Neuralgia/metabolism , Patch-Clamp Techniques , Piperidines/therapeutic use , Pyrazoles/therapeutic use , Rats , Structure-Activity Relationship , omega-Conotoxins/therapeutic useABSTRACT
This paper focused on adding a suitable lubrication effect at the interface between the rubber and mixer chamber wall on reducing the surface wear rate of the mixer chamber wall. In the research process, the contact model between the compound and internal mixer chamber wall was simplified to the pin-on-disc experimental model. The experimental results showed that the friction coefficient and the metal surface wear rate of the mixer chamber were reduced (by approximately 24%) by adding an appropriate amount of antifriction agent in the mixing process, while the comprehensive properties of the compound showed an improvement trend. By analyzing the surface elements of the rubber compound, the MoS2 with an anti-wear effect on the surface of the rubber compound can form a lubrication mechanism between the rubber, filler, and mixer chamber wall metal. Combined with the result of the comprehensive properties of rubber, which showed that although the appropriate amount of antifriction agent formed a lubrication protection mechanism between the rubber and the inner mixing chamber wall, the mechanism did not affect the friction behavior required for mixing. The study can effectively enhance the effective friction mixing and reduce the wear and power consumption of the mixing chamber caused by excess friction during the mixing process.
ABSTRACT
Inhibition of the S-adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A (MAT2A), has received significant interest in the field of medicinal chemistry due to its implication as a synthetic lethal target in cancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novel MAT2A inhibitors with distinct in vivo properties that may enhance their utility in treating patients. Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270, to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, AGI-41998, and a potent, but limited brain-penetrant compound, AGI-43192. We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS).
Subject(s)
Methionine Adenosyltransferase , Neoplasms , Brain/metabolism , Drug Design , Humans , Neoplasms/drug therapy , S-Adenosylmethionine/metabolismABSTRACT
A series of indazoles have been discovered as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided by both X-ray crystallography and solution activity resulted in lead-like compounds with good pharmaceutical properties.
Subject(s)
Drug Discovery , Fructokinases/antagonists & inhibitors , Indazoles/pharmacology , Pyrazoles/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Indazoles/chemical synthesis , Indazoles/chemistry , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel series of 4-azetidinyl-1-aryl-cyclohexanes containing indazole or benzoisoxazole moiety have been identified as potent CCR2 antagonists with high selectivity versus hERG.
Subject(s)
Indazoles/chemistry , Indazoles/pharmacology , Oxazoles/chemistry , Oxazoles/pharmacology , Receptors, CCR2/antagonists & inhibitors , Animals , Cell Line , Cyclohexanes/chemical synthesis , Cyclohexanes/chemistry , Cyclohexanes/pharmacokinetics , Cyclohexanes/pharmacology , Dogs , Drug Design , Humans , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , Oxazoles/chemical synthesis , Oxazoles/pharmacokinetics , Rats , Receptors, CCR2/metabolism , Structure-Activity Relationship , Trans-Activators/metabolism , Transcriptional Regulator ERGABSTRACT
A series of 4-azetidinyl-1-aryl-cyclohexanes as potent CCR2 antagonists with high selectivity over activity for the hERG potassium channel is discovered through divergent SARs of CCR2 and hERG.
Subject(s)
Azetidines/pharmacology , Drug Discovery , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Hippurates/pharmacology , Receptors, CCR2/antagonists & inhibitors , Azetidines/chemical synthesis , Azetidines/chemistry , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels/metabolism , Hippurates/chemical synthesis , Hippurates/chemistry , Humans , Molecular Structure , Receptors, CCR2/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
As a result of further SAR studies on a piperidinyl piperidine scaffold, we report the discovery of compound 44, a potent, orally bioavailable CCR2 antagonist. While having some in vitro hERG activity, this molecule was clean in an in vivo model of QT prolongation. In addition, it showed excellent efficacy when dosed orally in a transgenic murine model of acute inflammation.
Subject(s)
Amides/chemistry , Anti-Inflammatory Agents/chemistry , Receptors, CCR2/antagonists & inhibitors , Acute Disease , Administration, Oral , Amides/pharmacology , Amides/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Drug Evaluation, Preclinical , Humans , Inflammation/drug therapy , Mice , Mice, Transgenic , Rats , Receptors, CCR2/metabolism , Structure-Activity RelationshipABSTRACT
The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10â¯000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250).
Subject(s)
Enzyme Inhibitors/chemistry , Methionine Adenosyltransferase/antagonists & inhibitors , Purine-Nucleoside Phosphorylase/genetics , Binding Sites , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Homozygote , Humans , Methionine Adenosyltransferase/metabolism , Molecular Dynamics Simulation , Neoplasms/drug therapy , Purine-Nucleoside Phosphorylase/metabolism , S-Adenosylmethionine/metabolism , Structure-Activity RelationshipABSTRACT
The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP-/- cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.