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	Scott D Kuduk, Christina N Di Marco, Ronald K Chang, Michael R Wood, Kathy M Schirripa, June J Kim, Jenny M C Wai, Robert M DiPardo, Kathy L Murphy, Richard W Ransom, C Meacham Harrell, Duane R Reiss, Marie A Holahan, Jacquelynn Cook, J Fred Hess, Nova Sain, Mark O Urban, Cuyue Tang, Thomayant Prueksaritanont, Douglas J Pettibone, Mark G Bock
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 2 Pg. 272-82 (Jan 25 2007) ISSN: 0022-2623 [Print] United States
PMID	17228869 (Publication Type: Journal Article)
Chemical References	Acetamides Amides Aminobiphenyl Compounds Analgesics Anti-Inflammatory Agents, Non-Steroidal Benzoates Bradykinin B1 Receptor Antagonists Cyclopropanes methyl 3-chloro-3'-fluoro-4'-(1-(((1-((trifluoroacetyl)amino)cyclopropyl)carbonyl)amino)ethyl)-1,1'-biphenyl-2-carboxylate
Topics	Acetamides (chemical synthesis, pharmacokinetics, pharmacology) Administration, Oral Amides (chemical synthesis, pharmacokinetics, pharmacology) Aminobiphenyl Compounds (chemical synthesis, pharmacokinetics, pharmacology) Analgesics (chemical synthesis, chemistry, pharmacology) Animals Animals, Genetically Modified Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology) Benzoates (chemical synthesis, pharmacokinetics, pharmacology) Biological Availability Blood-Brain Barrier (metabolism) Bradykinin B1 Receptor Antagonists Brain (metabolism) CHO Cells Chlorocebus aethiops Cricetinae Cricetulus Cyclopropanes (chemical synthesis, pharmacokinetics, pharmacology) Female Humans Macaca mulatta Male Mice Rabbits Radioligand Assay Rats Species Specificity Spinal Cord (metabolism) Structure-Activity Relationship

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