Document Report Card

ID: ALA1139836

Journal: J Med Chem

Title: Development of orally bioavailable and CNS penetrant biphenylaminocyclopropane carboxamide bradykinin B1 receptor antagonists.

Authors: Kuduk SD, Di Marco CN, Chang RK, Wood MR, Schirripa KM, Kim JJ, Wai JM, DiPardo RM, Murphy KL, Ransom RW, Harrell CM, Reiss DR, Holahan MA, Cook J, Hess JF, Sain N, Urban MO, Tang C, Prueksaritanont T, Pettibone DJ, Bock MG.

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.

CiteXplore: 17228869

DOI: 10.1021/jm061094b