Regulatory Peptides 80 (1999) 13–26 Review Nonpeptide antagonists for kinin receptors * Maria Altamura , Stefania Meini, Laura Quartara, Carlo Alberto Maggi Menarini Ricerche S.p. A., via dei Sette Santi 3, I-50131 Firenze, Italy Received 3 November 1998; received in revised form 14 December 1998; accepted 15 December 1998 Abstract Kinins are a family of small peptides acting as mediators of inflammation and pain in the peripheral and central nervous system. The 1 2 3 4 5 6 7 8 9 two main ‘kinins’ in mammals are the nonapeptide bradykinin (BK, Arg -Pro -Pro -Gly -Phe -Ser -Pro -Phe -Arg ) and the decapeptide 0 1 2 3 4 5 6 7 8 9 10 kallidin (KD, [Lys ]-BK, Lys -Arg -Pro -Pro -Gly -Phe -Ser -Pro -Phe -Arg ). Their biological actions are mediated by two distinct receptors, termed B1 and B2. Kinin B1 and B2 receptor antagonists may be useful drugs endowed with analgesic and anti-inflammatory properties, with potential use in asthma, allergic rhinitis and other diseases. The first nonpeptide kinin B2 receptor antagonist, WIN 64338, was reported in 1993. Despite its low selectivity, the compound provided a reference for pharmacological and modeling studies. Several quinoline and imidazo[1,2-a]pyridine derivatives have been shown by Fujisawa to possess high affinity and selectivity for kinin B2 receptors. Among them, FR 173657 displayed excellent in vitro and in vivo antagonistic activity, while FR 190997 emerged as the first nonpeptide agonist for B2 receptor. Two structurally related Fournier compounds were recently published. Other kinin B2 receptor ligands were obtained by rational design, through library screening or from natural sources. The only example of a nonpeptide kinin B1 receptor ligand has been reported in a patent by Sanofi.  1999 Elsevier Science B.V. All rights reserved. Keywords: Bradykinin; Kallidin; B1 receptor; B2 receptor; FR 173657; FR 190997 1. Biology of kinins and kinin receptors the action of kallikreins on a high molecular weight form of kininogen; KD is produced in tissues by the action of Kinins are a family of small peptides which act as kallikreins on a low molecular weight form of kininogen mediators of inflammation and pain in the peripheral and [1]. central nervous system. The cascade of enzymatic steps Kinins are rapidly degraded by several enzymes and which determines the formation and degradation of kinins some metabolic steps produce biologically active metabo- has been elucidated, and detailed information on this issue lites as follows: (i) KD can be converted to BK by can be found in the excellent review of Bhoola et al. [1]. aminopeptidases and (ii) both BK and KD are cleaved by Briefly, kinins are released from large inactive pre- carboxypeptidase N (kininase I) which removes the C- 9 cursors (kininogens) under the action of several enzymes, terminal Arg residue to produce desArg -BK and 10 collectively known as kallikreins. In mammals the two desArg -KD. The latter peptides are biologically relevant 1 main ‘kinins’ are bradykinin (BK), a nonapeptide (Arg - since they act as selective agonists for the kinin B1 2 3 4 5 6 7 8 9 receptor (see below). Further degradation of kinins and Pro -Pro -Gly -Phe -Ser -Pro -Phe -Arg ), and kallidin, a 0 1 2 3 4 5 their des-Arg metabolites yields inactive compounds [1]. decapeptide (KD; [Lys ]-BK, Lys -Arg -Pro -Pro -Gly - 6 7 8 9 10 In mammals, the biological actions of kinins are me- Phe -Ser -Pro -Phe -Arg ). BK is produced in plasma by diated by two distinct receptors, termed B1 and B2, respectively (Table 1). The existence of these receptors was put forward in the early 1980s on the basis of a * sharply diverging pharmacological profile of kinin action Corresponding author. Tel.: 1 39-55-568-0616; fax 1 39-55-568- 0419; e-mail: maltamura@menarini-ricerche.it in selected isolated smooth muscle bioassays [2]. The 0167-0115 / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0167-0115(99)00003-8