title: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.forename: Christina N
authors.initials: CN
authors.lastname: Di Marco
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Chang
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.forename: Kathy M
authors.initials: KM
authors.lastname: Schirripa
authors.forename: June J
authors.initials: JJ
authors.lastname: Kim
authors.forename: Jenny M C
authors.initials: JM
authors.lastname: Wai
authors.forename: Robert M
authors.initials: RM
authors.lastname: DiPardo
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Murphy
authors.forename: Richard W
authors.initials: RW
authors.lastname: Ransom
authors.forename: C Meacham
authors.initials: CM
authors.lastname: Harrell
authors.forename: Duane R
authors.initials: DR
authors.lastname: Reiss
authors.forename: Marie A
authors.initials: MA
authors.lastname: Holahan
authors.forename: Jacquelynn
authors.initials: J
authors.lastname: Cook
authors.forename: J Fred
authors.initials: JF
authors.lastname: Hess
authors.forename: Nova
authors.initials: N
authors.lastname: Sain
authors.forename: Mark O
authors.initials: MO
authors.lastname: Urban
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Pettibone
authors.forename: Mark G
authors.initials: MG
authors.lastname: Bock
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000611:Aminobiphenyl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D065169:Bradykinin B1 Receptor Antagonists; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D013045:Species Specificity; D013116:Spinal Cord / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000577:Amides; D000611:Aminobiphenyl Compounds; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D065169:Bradykinin B1 Receptor Antagonists; D003521:Cyclopropanes; C517804:methyl 3-chloro-3'-fluoro-4'-(1-(((1-((trifluoroacetyl)amino)cyclopropyl)carbonyl)amino)ethyl)-1,1'-biphenyl-2-carboxylate