ABSTRACT
A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux.
Subject(s)
Alkenes/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Alkenes/chemical synthesis , Alkenes/chemistry , Amides/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037-0.15 nM range.
Subject(s)
Amides/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Amides/chemistry , StereoisomerismABSTRACT
A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP Ki=0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.
Subject(s)
Acetamides/chemistry , Calcitonin Gene-Related Peptide Receptor Antagonists , Spiro Compounds/chemistry , Acetamides/chemical synthesis , Acetamides/pharmacology , Animals , Cell Line , Drug Design , Humans , Rats , Receptors, Calcitonin Gene-Related Peptide/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
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
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
Antagonism of the bradykinin B1 receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists were designed that display low-nanomolar affinity for the human bradykinin B1 receptor and good bioavailability in the rat.
Subject(s)
Amides/chemical synthesis , Analgesics/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Bradykinin B1 Receptor Antagonists , Cyclopropanes/chemical synthesis , Pyridines/chemical synthesis , Amides/chemistry , Amides/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Biological Availability , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Drug Design , Humans , Molecular Conformation , Pyridines/chemistry , Pyridines/pharmacology , Rats , Stereoisomerism , 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.
Subject(s)
Benzodiazepines/chemical synthesis , Bradykinin Receptor Antagonists , Animals , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , CHO Cells , Cricetinae , Humans , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptor, Bradykinin B1 , Receptor, Bradykinin B2 , Structure-Activity RelationshipABSTRACT
A series of 2,3-diaminopyridine bradykinin B(1) antagonists was modified to mitigate the potential for bioactivation. Removal of the 3-amino group and incorporation of basic 5-piperazinyl carboxamides at the pyridine 5-position provided compounds with high affinity for the human B(1) receptor.