Non-peptide antagonists and agonists of the bradykinin B(2) receptor.

Abstract

Stimulation of the bradykinin (BK) B(2) receptor by kinins is associated with pathophysiological as well as pronounced beneficial effects. Consequently, interference with BK B(2) receptors by either antagonism or agonism offers promising therapeutic approaches for the development of drugs for the treatment of various human diseases. BK B(2) receptor antagonists may prove useful for the treatment of pathological situations caused by excessively increased local kinin concentrations, such as inflammation, tissue injury and pain. Beneficial effects of peptide BK B(2) receptor antagonists in perennial rhinitis, asthma and brain edema have already been demonstrated in clinical trials. On the other hand, kinins have also been identified as potent vasodilatory and organ-protective peptides. Therefore, BK B(2) receptor agonists may have the potential to become valuable therapeutics in the treatment of cardiovascular diseases such as hypertension, myocardial hypertrophy, myocardial infarction and arrhythmias as well as diabetic disorders. For both approaches, potent, selective and even orally active non-peptide compounds have been discovered recently. Prototypes of these novel third generation classes of compounds are the alkylphosphonium salt WIN-64338, the pseudopeptide NPC-18884, the thiosemicarbazide bradyzide and especially the imidazo[1,2-a]pyridine FR-167344 and the quinolines FR-173657 and LF-16.0687 as non-peptide BK B(2) receptor antagonists, whereas the 4-(2-pyridylmethoxy)-substituted quinoline FR-190997 and the 3-(2-pyridylmethyl)-substituted benzimidazole FR-191413 emerged as non-peptide BK B(2) receptor agonists. These antagonists and agonists of the BK B(2) receptor have already demonstrated efficacy a various animal models of human diseases, which offers promising therapeutic approaches for the development of drugs for the treatment or even prevention of a variety of severe human diseases either via stimulation or via blockade of BK B(2) receptors.