Development of orally bioavailable and CNS penetrant biphenylaminocyclopropane carboxamide bradykinin B1 receptor antagonists.
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.
Kuduk
Scott D
SD
Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, USA.
Di Marco
Christina N
CN
Chang
Ronald K
RK
Wood
Michael R
MR
Schirripa
Kathy M
KM
Kim
June J
JJ
Wai
Jenny M C
JM
DiPardo
Robert M
RM
Murphy
Kathy L
KL
Ransom
Richard W
RW
Harrell
C Meacham
CM
Reiss
Duane R
DR
Holahan
Marie A
MA
Cook
Jacquelynn
J
Hess
J Fred
JF
Sain
Nova
N
Urban
Mark O
MO
Tang
Cuyue
C
Prueksaritanont
Thomayant
T
Pettibone
Douglas J
DJ
Bock
Mark G
MG
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
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