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
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
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
Subject(s)
Amides/chemistry , Complement C1s/antagonists & inhibitors , Drug Design , Polyethylene Glycols/chemistry , Protease Inhibitors/chemical synthesis , Thiophenes/chemistry , Animals , Complement C1s/metabolism , Half-Life , Protease Inhibitors/chemistry , Protease Inhibitors/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
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
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
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.
Subject(s)
Complement C1s/antagonists & inhibitors , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Animals , Binding Sites , Half-Life , Models, Molecular , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.
Subject(s)
Arylsulfonates/chemical synthesis , Complement C1s/antagonists & inhibitors , Serine Proteinase Inhibitors/chemical synthesis , Amidines/chemical synthesis , Amidines/pharmacology , Angioedema/drug therapy , Arylsulfonates/pharmacology , Fibrinolysin/pharmacology , Graft Rejection/drug therapy , Humans , Myocardial Ischemia/drug therapy , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Tetradecanoylphorbol Acetate/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Thrombin/pharmacology , Urokinase-Type Plasminogen Activator/pharmacologyABSTRACT
Activation of the classical pathway of complement has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury and acute transplant rejection. The trypsin-like serine protease C1s represents a pivotal upstream point of control in the classical pathway of complement activation and is therefore likely to be a useful target in the therapeutic intervention of these disease states. A series of thiopheneamidine-based inhibitors of C1s has been optimized to give a 70 nM inhibitor that inhibits the classical pathway of complement activation in vitro.
Subject(s)
Complement Inactivator Proteins/chemical synthesis , Complement Pathway, Classical/drug effects , Pyrazoles/chemical synthesis , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Thiazoles/chemical synthesis , Thiophenes/chemical synthesis , Binding Sites/physiology , Complement C1/metabolism , Complement Inactivator Proteins/pharmacology , Complement Pathway, Classical/physiology , Humans , Myocardial Ischemia/drug therapy , Myocardial Ischemia/enzymology , Pyrazoles/pharmacology , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thiazoles/pharmacology , Thiophenes/pharmacologyABSTRACT
A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with but possessing improved solubility.