Benzodiazepines as potent and selective bradykinin B1 antagonists

…, JJ Kim, W Han, BD Dorsey, CF Homnick…

Index: 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. Journal of Medicinal Chemistry, 2003 , vol. 46, # 10 p. 1803 - 1806

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Citation Number: 63

Abstract

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.