Non-peptide bradykinin B2 receptor ligands possessing the substituted quinolinyl moiety: Pharmacological properties and prospective clinical uses.

Bradykinin is a nonapeptide derived from the cleavage of circulating kininogens by plasma or tissue kallikreins and is endowed with powerful pharmacologic actions, such as the production of protein-rich exudates and vasodilation. The widely expressed B2 receptor for bradykinin (a G protein-coupled receptor) has been the focus of intense drug development efforts for more than 4 decades, with marked differences in affinities and competitiveness for synthetic antagonists across mammalian species. Many non-peptide ligands of the human B2 receptor have been developed by various industrial organizations. A recurring substituted 8-[(2,6-dichlorophenyl)methoxy]-2-methylquinolinyl ("quinolyl") moiety, or variants thereof, was explored by several pharmaceutical organizations. FR173657, fasitibant, anatibant, deucrictibant and Compound 3 (the non-deuterated version of deucrictibant) are examples of competitive antagonists of the human B2 receptor, some of which having reached the stage of clinical trials. Other compounds structurally related to the common moiety, such as FR190997 and Compound 47a, are partial or nearly full agonists of the B2 receptor. The ongoing clinical development of deucrictibant for the treatment of hereditary angioedema is a first step in clarifying the therapeutic potential of orally bioavailable B2 receptor antagonists.