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
GPR40 partial agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus with clinical proof of concept. Most of the GPR40 agonists in the literature have a carboxylic acid functional group, which may pose a risk for idiosyncratic drug toxicity. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid bioisostere was identified. This series of compounds features a benzo[b]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose in a SD rat oGTT model.
Subject(s)
Drug Discovery , Receptors, G-Protein-Coupled/agonists , Tetrazoles/pharmacology , Thiophenes/pharmacology , Animals , Dogs , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Rats , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Tetrazoles/chemistry , Thiophenes/chemistryABSTRACT
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
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
GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due to increased insulin and GLP-1 secretion, with the added benefit of promoting weight loss. In our search for potent GPR40 full agonists, we discovered a superagonist which displayed excellent in vitro potency and superior efficacy in the Gαs-mediated signaling pathway. Most synthetic GPR40 agonists have a carboxylic acid headgroup, which may cause idiosyncratic toxicities, including drug-induced-liver-injury (DILI). With a methyl group and a fluorine atom substituted at the α-C of the carboxylic acid group, 19 is not only highly efficacious in lowering glucose and body weight in rodent models but also has a low DILI risk due to its stable acylglucuronide metabolite.
ABSTRACT
A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.
Subject(s)
Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Lung/drug effects , Receptors, Interleukin-8B/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonic Acids/chemistry , Sulfonylurea Compounds/chemistry , Administration, Oral , Animals , Animals, Newborn , Biological Availability , Bronchoalveolar Lavage , Carboxylic Acids/pharmacokinetics , Chemotaxis/drug effects , Cytochrome P-450 Enzyme System/metabolism , Humans , Hyperoxia , Lung/metabolism , Lung Injury , Molecular Structure , Neutrophils/metabolism , Rabbits , Rats , Structure-Activity RelationshipABSTRACT
A series of novel 5-aminomethyl-1H-benzimidazole based inhibitors of Itk were prepared. Structure-activity relationships, selectivity and cell activity are reported for this series. Compound 2, a potent and selective antagonist of Itk, inhibited anti-CD3 antibody induced IL-2 production in vivo in mice.
Subject(s)
Benzimidazoles/administration & dosage , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis , Chemistry, Pharmaceutical/methods , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/chemistry , Administration, Oral , Animals , Benzimidazoles/pharmacology , CD3 Complex/biosynthesis , Drug Design , Humans , Inhibitory Concentration 50 , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Models, Chemical , Structure-Activity Relationship , T-Lymphocytes/cytologyABSTRACT
A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.
Subject(s)
Amides/chemistry , Benzimidazoles/chemistry , Carboxylic Acids/chemistry , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Microsomes, Liver/metabolism , Protein-Tyrosine Kinases/chemistry , Animals , Benzimidazoles/chemical synthesis , Carboxylic Acids/chemical synthesis , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Mice , Models, Chemical , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
Subject(s)
Benzimidazoles/chemistry , Chemistry, Pharmaceutical/methods , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Benzimidazoles/chemical synthesis , Binding Sites , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Chemical , Protein Binding , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Pyrrolidin-2-one (gamma-lactam) derivatives have shown a wide range of activities as ligands to diverse receptors, e.g., integrin, CCR5, and CCK. Therefore, we have prepared a large library of these derivatives for high-throughput screening against various protein targets, after developing a synthesis of pyrrolidin-2-ones on solid phase. Exploration of the ring formation was key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-protected amino acids and subsequent deprotection of the Fmoc group were accomplished readily. The resulting resin-bound primary amines were treated with beta-monomethyl itaconate under gentle heat in a mixture of methanol and toluene to yield the desired intermediates. Finally, saponification, amide formation, and cleavage from the resin led to the production of a library of 12,000 pyrrolidin-2-one derivatives. These products were isolated as diastereomeric mixtures of high purity and were obtained in good yields.
ABSTRACT
The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail.