Development of Orally Bioavailable and CNS Penetrant Biphenylaminocyclopropane Carboxamide Bradykinin B1 Receptor Antagonists

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.