Benzodiazepines as Potent and Selective Bradykinin B1 Antagonists

• Published in: Journal of medicinal chemistry Vol. 46; no. 10; pp. 1803 - 1806
• Main Authors: Wood, Michael R, Kim, June J, Han, Wei, Dorsey, Bruce D, Homnick, Carl F, DiPardo, Robert M, Kuduk, Scott D, MacNeil, Tanya, Murphy, Kathy L, Lis, Edward V, Ransom, Richard W, Stump, Gary L, Lynch, Joseph J, O'Malley, Stacey S, Miller, Patricia J, Chen, Tsing-Bau, Harrell, Charles M, Chang, Raymond S. L, Sandhu, Punam, Ellis, Joan D, Bondiskey, Peter J, Pettibone, Douglas J, Freidinger, Roger M, Bock, Mark G
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 08.05.2003
• Subjects: Analgesics; Animals; Benzodiazepines - chemical synthesis; Benzodiazepines - chemistry; Benzodiazepines - pharmacology; Biological and medical sciences; Bradykinin Receptor Antagonists; CHO Cells; Cricetinae; Humans; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Structure-Activity Relationship; Intraperitoneal administration; Cyclohexane derivatives; Intravenous administration; Rat; Nitrogen heterocycle; Lactam; Selectivity; B1 bradykinin receptor; Hyperalgesia; Pyridine derivatives; Structure activity relation; Piperidine derivatives; Bicyclic compound; Peptidergic receptor; Ureas; Aromatic compound; Antagonist; Chemical synthesis; Human; Rodentia; Benzene derivatives; Oral administration; Bioavailability; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Analgesic; Treatment; Animal; Affinity; Piperazine derivatives; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm034020y

Antagonism of the bradykinin B1 receptor was demonstrated to be a potential treatment for chronic pain and inflammation. Novel benzodiazepines were designed that display subnanomolar affinity for the bradykinin B1 receptor (K i = 0.59 nM) and high selectivity against the bradykinin B2 receptor (K i > 10 μM). In vivo efficacy, comparable to morphine, was demonstrated for lead compounds in a rodent hyperalgesia model.