title: From bradykinin B2 receptor antagonists to orally active and selective bradykinin B1 receptor antagonists.
abstract: The bradykinin (BK) B1 receptor is an attractive target for the treatment of chronic pain and inflammation. Starting from a dual B1 and B2 antagonist, novel antagonists were designed that display low-nanomolar affinity for human B1 receptor and selectivity over B2. Initially, potent imidazoline derivatives were studied, but these compounds suffered from low bioavailability. This issue could be overcome by the use of less basic amino derivatives leading to orally active compounds.
authors.affiliation: Department of Chemical Design and Synthesis, Clinical Candidate Selection, Laboratoires Fournier, 50 Rue de Dijon, 21121 Daix, France. martine.barth@abbott.com
authors.forename: Martine
authors.initials: M
authors.lastname: Barth
authors.forename: Michel
authors.initials: M
authors.lastname: Bondoux
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Luccarini
authors.forename: Vincent
authors.initials: V
authors.lastname: Peyrou
authors.forename: Pierre
authors.initials: P
authors.lastname: Dodey
authors.forename: Didier
authors.initials: D
authors.lastname: Pruneau
authors.forename: Christine
authors.initials: C
authors.lastname: Massardier
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Paquet
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D048288:Imidazolines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D010147:Pain Measurement; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000700:Analgesics; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D048288:Imidazolines; D010879:Piperazines; D010880:Piperidines; D013449:Sulfonamides