Nonpeptide antagonists for kinin receptors

Kinins are a family of small peptides acting as mediators of inflammation a nd pain in the peripheral and central nervous system. The two main 'kinins' in mammals are the nonapeptide bradykinin (BK, Arg(1)-Pro(2)-Pro(3)-Gly(4) -Phe(5)-Ser(6)-Pro(7)-Phe(8)-Arg(9)) and the decapeptide kallidin (KD, [Lys (0)]-BK, Lys(1)-Arg(2)-Pro(3)-Pro(4)-Gly(5)-Phe(6)-Ser(7)-Pro(8)-Phe(9)-Arg (10)). Their biological actions are mediated by two distinct receptors, ter med B1 and B2. Kinin B1 and B2 receptor antagonists may be useful drugs end owed with analgesic and anti-inflammatory properties, with potential use in asthma, allergic rhinitis and other diseases. The first nonpeptide kinin B 2 receptor antagonist, WIN 64338, was reported in 1993. Despite its low sel ectivity, the compound provided a reference for pharmacological and modelin g studies. Several quinoline and imidazo[1,2-a]pyridine derivatives have be en shown by Fujisawa to possess high affinity and selectivity for kinin B2 receptors. Among them, FR 173657 displayed excellent in vitro and in vivo a ntagonistic activity, while FR 190997 emerged as the first nonpeptide agoni st for B2 receptor. Two structurally related Fournier compounds were recent ly published. Other kinin B2 receptor ligands were obtained by rational des ign, through library screening or from natural sources. The only example of a nonpeptide kinin B1 receptor ligand has been reported in a patent by San ofi. (C) 1999 Elsevier Science B.V. All rights reserved.