Abstract
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.
MeSH terms
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Acetamides / chemical synthesis*
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Acetamides / pharmacokinetics
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Acetamides / pharmacology
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Administration, Oral
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Amides / chemical synthesis*
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Amides / pharmacokinetics
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Amides / pharmacology
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Aminobiphenyl Compounds / chemical synthesis*
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Aminobiphenyl Compounds / pharmacokinetics
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Aminobiphenyl Compounds / pharmacology
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Analgesics / chemical synthesis
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Animals, Genetically Modified
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Benzoates / chemical synthesis*
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Benzoates / pharmacokinetics
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Benzoates / pharmacology
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Biological Availability
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Blood-Brain Barrier / metabolism
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Bradykinin B1 Receptor Antagonists*
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Brain / metabolism*
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CHO Cells
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Chlorocebus aethiops
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Cricetinae
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Cricetulus
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Cyclopropanes / chemical synthesis*
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Cyclopropanes / pharmacokinetics
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Cyclopropanes / pharmacology
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Female
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Humans
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Macaca mulatta
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Male
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Mice
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Rabbits
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Radioligand Assay
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Rats
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Species Specificity
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Spinal Cord / metabolism*
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Structure-Activity Relationship
Substances
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Acetamides
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Amides
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Aminobiphenyl Compounds
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Analgesics
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Anti-Inflammatory Agents, Non-Steroidal
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Benzoates
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Bradykinin B1 Receptor Antagonists
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Cyclopropanes
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methyl 3-chloro-3'-fluoro-4'-(1-(((1-((trifluoroacetyl)amino)cyclopropyl)carbonyl)amino)ethyl)-1,1'-biphenyl-2-carboxylate