ABSTRACT
A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition.
Subject(s)
Nerve Tissue Proteins/antagonists & inhibitors , Sodium Channel Blockers/chemistry , Acid Sensing Ion Channels , Amidines/chemistry , Amiloride/chemistry , Animals , Nerve Tissue Proteins/metabolism , Rats , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolism , Structure-Activity RelationshipABSTRACT
Incorporation of hydroxycycloalkyl fused pyridone carboxylic acids in lieu of quinolone carboxylic acids enhance free fraction without increased susceptibility to P-glycoprotein transport.
Subject(s)
Carboxylic Acids/pharmacology , Pyridones/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Allosteric Regulation , Animals , Carboxylic Acids/chemistry , Mice , Protein Transport , RatsABSTRACT
A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Subject(s)
Amidines/chemistry , Chemistry, Pharmaceutical/methods , Sodium Channels/chemistry , Acid Sensing Ion Channels , Animals , Drug Design , Electrophysiology , Indoles/chemistry , Inhibitory Concentration 50 , Ion Channels/chemistry , Male , Models, Chemical , Naproxen/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of amiloride derivatives modified at the 5-position of the pyrazine ring were evaluated as inhibitors of acid-sensing ion channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Subject(s)
Amiloride/analogs & derivatives , Chemistry, Pharmaceutical/methods , Nerve Tissue Proteins/chemistry , Pain/drug therapy , Sodium Channels/chemistry , Acid Sensing Ion Channels , Acidosis , Amiloride/chemistry , Amines/chemistry , Animals , Drug Design , Electrophysiology , Inhibitory Concentration 50 , Male , Models, Chemical , Pyrazines/chemistry , Rats , Rats, Sprague-DawleyABSTRACT
A series of carbo- and heterocyclic alpha-hydroxy amide-derived bradykinin B1 antagonists was prepared and evaluated. A 4,4-difluorocyclohexyl alpha-hydroxy amide was incorporated along with a 2-methyl tetrazole in lieu of an oxadiazole to afford a suitable compound with good pharmacokinetic properties, CNS penetration, and clearance by multiple metabolic pathways.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Bradykinin B1 Receptor Antagonists , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Amides/chemistry , Amides/pharmacokinetics , Animals , Central Nervous System/drug effects , Combinatorial Chemistry Techniques , Drug Design , Humans , Molecular Structure , Rats , Structure-Activity Relationship , Tetrazoles/chemistry , Tetrazoles/pharmacokineticsABSTRACT
The design and synthesis of a novel class of human bradykinin B1 antagonists featuring difluoroethyl ether and isoxazole carboxamide moieties are disclosed. Compound 7g displayed excellent pharmacokinetic properties, efficient ex vivo receptor occupancy, and low potential for P450 induction via PXR activation.
Subject(s)
Bradykinin B1 Receptor Antagonists , Isoxazoles/pharmacology , Receptors, Steroid/drug effects , Administration, Oral , Animals , Biological Availability , Dogs , Humans , Isoxazoles/pharmacokinetics , Macaca mulatta , Pregnane X Receptor , Rats , Rats, Sprague-DawleyABSTRACT
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Subject(s)
Amides/pharmacology , Bradykinin B1 Receptor Antagonists , Amides/chemistry , Amides/pharmacokinetics , Animals , Biological Availability , Blood-Brain Barrier , Cytochrome P-450 Enzyme Inhibitors , Dogs , Half-Life , Humans , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
SAR study of the biphenyl region of cyclopropanecarboxamide derived bradykinin B(1) antagonists was examined. Incorporation of a pyridine in place of the proximal phenyl ring and chlorination of the distal phenyl ring proved to be well tolerated and provided compounds with improved pharmacokinetic profiles, CNS penetration, and enhanced receptor occupancy.
Subject(s)
Amides/chemistry , Bradykinin B1 Receptor Antagonists , Animals , Central Nervous System/drug effects , Chemistry, Pharmaceutical/methods , Chlorine/chemistry , Cyclopropanes/chemistry , Drug Design , Humans , Models, Chemical , Phenol/chemistry , Pyridines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
A series of biphenylaminocyclopropane carboxamide based bradykinin B1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery that the replacement of the trifluoropropionamide in the lead structure with polyhaloacetamides, particularly a trifluoroacetamide, significantly reduced P-glycoprotein mediated efflux for the series proved essential. One of these novel bradykinin B1 antagonists (13b) also exhibited suitable pharmacokinetic properties and efficient ex vivo receptor occupancy for further development as a novel approach for the treatment of pain and inflammation.
Subject(s)
Acetamides/chemical synthesis , Amides/chemical synthesis , Aminobiphenyl Compounds/chemical synthesis , Benzoates/chemical synthesis , Bradykinin B1 Receptor Antagonists , Brain/metabolism , Cyclopropanes/chemical synthesis , Spinal Cord/metabolism , Acetamides/pharmacokinetics , Acetamides/pharmacology , Administration, Oral , Amides/pharmacokinetics , Amides/pharmacology , Aminobiphenyl Compounds/pharmacokinetics , Aminobiphenyl Compounds/pharmacology , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Animals , Animals, Genetically Modified , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzoates/pharmacokinetics , Benzoates/pharmacology , Biological Availability , Blood-Brain Barrier/metabolism , CHO Cells , Chlorocebus aethiops , Cricetinae , Cricetulus , Cyclopropanes/pharmacokinetics , Cyclopropanes/pharmacology , Female , Humans , Macaca mulatta , Male , Mice , Rabbits , Radioligand Assay , Rats , Species Specificity , Structure-Activity RelationshipABSTRACT
This study used behavioural and in vivo electrophysiological paradigms to examine the effects of systemic and spinal administration of a bradykinin B1 receptor antagonist, compound X, on acute nociceptive responses in the rat. In behavioural experiments, compound X significantly increased the latency to withdraw the hindpaw from a radiant heat source after both intravenous and intrathecal administration, without affecting motor performance on the rotarod. In electrophysiological experiments, both intravenous and direct spinal administration of compound X attenuated the responses of single dorsal horn neurones to noxious thermal stimulation of the hindpaw. These data show that the antinociceptive effects of a bradykinin B1 receptor antagonist are mediated, at least in part, at the level of the spinal cord and suggest a role for spinal bradykinin B1 receptors in acute nociception.
Subject(s)
Amides/pharmacokinetics , Bradykinin B1 Receptor Antagonists , Naphthalenes/pharmacokinetics , Pain Measurement/methods , Pyrrolidines/pharmacokinetics , Spinal Cord/drug effects , Amides/administration & dosage , Animals , Carrageenan/administration & dosage , Carrageenan/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Electrophysiology/methods , Foot , Hindlimb , Hot Temperature/adverse effects , Hyperalgesia/etiology , Hyperalgesia/physiopathology , Hyperalgesia/prevention & control , Hypersensitivity/etiology , Hypersensitivity/physiopathology , Injections, Intravenous , Injections, Spinal , Male , Morphine/pharmacology , Naphthalenes/administration & dosage , Nociceptors/drug effects , Nociceptors/physiology , Psychomotor Performance/drug effects , Pyrrolidines/administration & dosage , Rats , Rats, Sprague-Dawley , Spinal Cord/physiologyABSTRACT
An efficient method for the synthesis of fluoropyridines via the fluorodenitration reaction is reported. The reaction is mediated by tetrabutylammonium fluoride (TBAF) under mild conditions without undue regard to the presence of water. The fluorodenitration is general for 2- or 4-nitro-substituted pyridines, while 3-nitropyridines require attendant electron-withdrawing groups for the reaction to proceed efficiently. Nitropyridines also undergo hydroxy- and methoxydenitration under mild conditions in the presence of the corresponding tetrabutylammonium species. [reaction: see text]
Subject(s)
Nitro Compounds/chemistry , Pyridines/chemical synthesis , Quaternary Ammonium Compounds , Models, Molecular , NitratesABSTRACT
Antagonists of the B1 bradykinin receptor (B1R) offer the promise of novel therapeutic agents for the treatment of inflammatory and neuropathic pain. However, the in vivo characterization of the pharmacodynamics of B1R antagonists is hindered by the low level of B1R expression in healthy tissue and the profound species selectivity exhibited by many compounds for the human B1R. To circumvent these issues, we generated a transgenic rat expressing the human B1R under the control of the neuron-specific enolase promoter. Membranes prepared from whole brain homogenates of heterozygous transgenic rats indicate a B1R expression level of 30 to 40 fmol/mg; there is no detectable B1R expression in control nontransgenic rats. The pharmacological profile of the B1R expressed in the transgenic rat matches that expected of the human, but not the rat receptor. The mapping of the transgene insertion site to rat chromosome 1 permitted the development of a reliable assay for the identification of homozygous transgenic rats. Significantly, homozygous transgenic rats express 2-fold more B1R than heterozygous animals. Autoradiographic analyses of tissue sections from transgenic rats reveal that the B1R is broadly expressed in both the brain and spinal cord. The human B1R expressed in the transgenic rat functions in an in vitro contractile assay and thus has the potential to elicit a functional response in vivo. Using the humanized B1R transgenic rat, an assay was developed that is suitable for the routine evaluation of a test compound's ability to occupy the human B1R in the central nervous system.
Subject(s)
Animals, Genetically Modified/genetics , Models, Animal , Rats/genetics , Receptor, Bradykinin B1/biosynthesis , Receptor, Bradykinin B1/genetics , Animals , Animals, Genetically Modified/metabolism , Brain/drug effects , Brain/metabolism , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Female , Humans , Ileum/drug effects , Ileum/metabolism , Male , Peptide Fragments/pharmacology , Protein Binding/drug effects , Protein Binding/physiologyABSTRACT
Bradykinin (BK) plays an important role in the pathophysiological processes accompanying pain and inflammation. Selective bradykinin B1 receptor antagonists have been shown to be anti-nociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. We have explored chemical modifications in a series of dihydroquinoxalinone sulfonamides to evaluate the effects of various structural changes on biological activity. The optimization of a screening lead compound, facilitated by a homology model of the BK B1 receptor, culminated in the discovery of a potent human BK B1 receptor antagonist. Results from site-directed mutagenesis studies and experiments in an animal pain model are presented.
Subject(s)
Bradykinin Receptor Antagonists , Quinoxalines/chemistry , Quinoxalines/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Animals , Binding Sites , Dogs , Humans , Kinetics , Models, Molecular , Mutagenesis, Site-Directed , Pain Measurement/drug effects , Rabbits , Rats , Receptor, Bradykinin B1 , Receptors, Bradykinin/chemistry , Receptors, Bradykinin/genetics , Receptors, Bradykinin/metabolism , Structure-Activity RelationshipABSTRACT
Antagonism of the bradykinin B(1) receptor was demonstrated to be a potential treatment for chronic pain and inflammation. Novel benzodiazepines were designed that display subnanomolar affinity for the bradykinin B(1) receptor (K(i) = 0.59 nM) and high selectivity against the bradykinin B(2) receptor (K(i) > 10 microM). In vivo efficacy, comparable to morphine, was demonstrated for lead compounds in a rodent hyperalgesia model.