Elsevier

Regulatory Peptides

Volume 80, Issues 1–2, 17 March 1999, Pages 13-26
Regulatory Peptides

Review
Nonpeptide antagonists for kinin receptors

https://doi.org/10.1016/S0167-0115(99)00003-8Get rights and content

Abstract

Kinins are a family of small peptides acting as mediators of inflammation and pain in the peripheral and central nervous system. The two main `kinins' in mammals are the nonapeptide bradykinin (BK, Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9) and the decapeptide kallidin (KD, [Lys0]-BK, Lys1-Arg2-Pro3-Pro4-Gly5-Phe6-Ser7-Pro8-Phe9-Arg10). 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.

Section snippets

Biology of kinins and kinin receptors

Kinins are a family of small peptides which act as mediators of inflammation and pain in the peripheral and central nervous system. The cascade of enzymatic steps which determines the formation and degradation of kinins has been elucidated, and detailed information on this issue can be found in the excellent review of Bhoola et al. [1].

Briefly, kinins are released from large inactive precursors (kininogens) under the action of several enzymes, collectively known as kallikreins. In mammals the

Biological actions and pathophysiological relevance of kinins

Kinins produce a wide variety of biological effects, which include vasodilation and modulation of vascular permeability, smooth muscle contraction, recruitment and priming of inflammatory cells, induction of pain, modulation of transmitter release, stimulation of cell division etc. [12].

The development of peptide antagonists for kinin receptors, and particularly, the development of the high affinity and metabolically stable peptide antagonist for kinin B2 receptors, icatibant (Hoe 140, dArg1-Arg

First examples of nonpeptide antagonists: WIN 64338 and the Sterling Winthrop model

Up to 1993, and despite a considerable effort in this field, no examples of selective nonpeptide kinin antagonists have been reported in the literature 21, 22.

By 1993, Sterling Winthrop researchers started to publish their results about the design [23], chemical synthesis [24], structure–activity relationships [25]and pharmacology 26, 27of the first nonpeptide competitive kinin B2 antagonist, WIN 64338 (Fig. 2, Table 2).

According to these reports, a random screening carried out on a large

Nonpeptide antagonists and agonists from Fujisawa

Researchers from Fujisawa have synthesized a number of quinoline and imidazo[1,2-a]pyridine derivatives 34, 35, 36, 37which possess high binding affinity and selectivity for kinin B2 receptors. These compounds were developed through medicinal chemistry efforts performed around nonpeptide lead compounds discovered by random screening in a series of angiotensin II AT1 receptor antagonists [38].

Several terms of this series (Fig. 3 and Fig. 4; Table 2 and Table 3) have been disclosed which possess

Antagonists structurally related to FR 173657 and other quinolines

A number of derivatives structurally related to Fujisawa compounds have been recently disclosed in the patent literature by Fournier 60, 61, 62, 63, 64and Hoechst 65, 66, 67as kinin B2 receptor antagonists.

The main structural novelty in the Fournier derivatives (Fig. 10) is the presence of a central sulfonamide linkage replacing the N-methylamide present in Fujisawa compounds. As in FR 173657, a dichlorobenzene-linked terminal quinoline stands at one side, while the other side varies from a

Miscellaneous B2 antagonists

Molecular modeling studies on the potent peptide kinin B2 receptor antagonist CP-0597, d-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-d-Tic-NChg-Arg [76]led Cortech to the rational design of novel nonpeptide antagonists, based on the assumption that a type II′ β-turn conformation for the C-terminal region of the decapeptide CP-0597 is important for the antagonist activity at B2 receptor, and that the interaction of the C-terminal tripeptide d-Tic-NChg-Arg with the receptor is essential for high affinity binding

Nonpeptide kinin antagonists from natural sources

The recent literature reports only two examples, both from Merck, of nonpeptide kinin antagonists isolated from natural sources.

Martinelline (Fig. 17) 84, 85, a pyrroloquinoline alkaloid isolated from the roots of the tropical plant Martinella iquitosensis, showed affinity for both B1 and B2 receptors (B1: IC50=6.4 μM, [3H]-[des-Arg10]-kallidin binding in rabbit aorta smooth muscle cells; B2: IC50=0.25 μM, [3H]BK binding to GPI). The compound is not selective since it possesses binding affinity

Nonpeptide kinin B1 antagonists

The only known examples of nonpeptide kinin B1 antagonists are a number of Sanofi compounds (Fig. 18), disclosed in a 1997 patent [87]. The affinity for kinin B1 receptor was determined using membranes of MRC5 cells and found to be 0.1 nM. One example of this series is shown as structure (5), Fig. 18.

Conclusions

The evidence summarized in this review documents the efforts made by different research groups in the discovery of nonpeptide kinin receptor antagonists. A number of compounds of this type are now available for studying the distribution and function of kinin B2 receptors, and their use in animal models of disease will undoubtedly expand our knowledge on the role of B2 receptors in pathology and physiology. It appears likely that some of the ligands described in this review or their close

References (94)

  • SM Dankwardt et al.

    Nonpeptide bradykinin antagonist analogs based on a model of a Sterling Winthrop nonpeptide bradykinin antagonists overlapped with cyclic hexapeptide bradykinin antagonist peptides

    BioOrg Med Chem Lett

    (1997)
  • N Inamura et al.

    Pharmacological characterization of a novel, orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344

    Eur J Pharmacol

    (1997)
  • DG Sawutz et al.

    Characterization of bradykinin B2 receptors on human IMR-90 lung fibroblasts: stimulation of 45Ca2+ efflux by d-Phe7 substituted bradykinin analogues

    Eur J Pharmacol

    (1992)
  • N-E Rhaleb et al.

    Pharmacological characterization of a new highly potent B2 receptor antagonist (HOE 140: d-Arg-[Hyp3,Thi5,d-Tic7,Oic8]bradykinin)

    Eur J Pharmacol

    (1992)
  • T Sakamoto et al.

    Effect of Hoe 140, a new bradykinin receptor antagonist, on bradykinin- and platelet-activating factor-induced bronchoconstriction and airway microvascular leakage in guinea pig

    Eur J Pharmacol

    (1992)
  • D Regoli et al.

    Bradykinin receptor types and B2 subtypes

    Life Sci

    (1994)
  • KD Bhoola et al.

    Bioregulation of kinins: kallikreins, kininogens and kininases

    Pharmacol Rev

    (1992)
  • D Regoli et al.

    Pharmacology of bradykinin and related kinins

    Pharmacol Rev

    (1980)
  • Marceau F. Kinin B1 receptor induction and inflammation. In: Farmer SG, editor. The kinin system. London: Academic...
  • AA Roscher et al.

    Regulation of bradykinin action at the receptor level

    J Cardiovasc Pharmacol

    (1990)
  • F Marceau et al.

    The B1 receptors for kinins

    Pharmacol Rev

    (1998)
  • Hall JM, Morton IKM. The pharmacology and immunopharmacology of kinin receptors. In: Farmer SG, editor. The kinin...
  • FJ Hock et al.

    Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies

    Br J Pharmacol

    (1991)
  • K Wirth et al.

    Hoe 140 a new potent and long acting bradykinin-antagonist: in vivo studies

    Br J Pharmacol

    (1991)
  • Farmer SG. The kallikrein–kinin system in asthma and acute respiratory distress syndrome. In: Farmer SG, editor. The...
  • Griesbacher T, Lembeck F. Putative role of bradykinin and the kinin system in pancreatitis. In: Farmer SG, editor. The...
  • Maggi CA. Bradykinin as an inflammatory mediator in the urinary tract. In: Farmer SG, editor. The kinin system. London:...
  • DJ Kyle

    Structure based drug design: progress toward the discovery of the elusive bradykinin receptor antagonists

    Curr Pharm Des

    (1995)
  • Dodey P, Luccarini J-M, Martinez J, Amblard M, Daffix I. Pseudopeptide agonists of bradykinin B2 receptors — for...
  • Wagner A, Breipohl G, Heitsch H, Gerhards H, Noelken G, Wirth K, Schölkens B. Preparation of tri- and tetrapeptides as...
  • Calixto JB, Yunes RA, Rae GA, Medeiros YS. Nonpeptide bradykinin antagonists. In: Burch RM, editor. Bradykinin...
  • DJ Kyle et al.

    A survey of bradykinin receptors and their antagonists

    Curr Opin Invest Drugs

    (1993)
  • JM Salvino et al.

    Design of potent non-peptide competitive antagonists of the human bradykinin B2 receptor

    J Med Chem

    (1993)
  • DG Sawutz et al.

    The nonpeptide WIN 64338 is a bradykinin B2 receptor antagonist

    Proc Natl Acad Sci USA

    (1994)
  • DG Sawutz et al.

    Pharmacology and structure activity relationships of the nonpeptide bradykinin receptor antagonist WIN 64338

    Can J Physiol Pharmacol

    (1995)
  • JM Salvino et al.

    Conformational analysis of bradykinin by annealed molecular dynamics and comparison to NMR derived conformations

    J Comput Chem

    (1993)
  • KJ Wirth et al.

    Kinin receptor antagonists: unique probes in basic and clinical research

    Can J Physiol Pharmacol

    (1995)
  • S Klutchko et al.

    Synthesis of novel angiotensin converting enzyme inhibitor quinapril and related compounds. A divergence of structure–activity relationships for non-sulfhydryl and sulfhydryl types

    J Med Chem

    (1986)
  • Oku T, Kayakiri H, Satoh S, Abe Y, Sawada Y, Tanaka H. Imidazo[1,2-a]pyridines as bradykinin antagonists. European...
  • Oku T, Kayakiri H, Satoh S, et al. Heterocyclic compounds as bradykinin antagonists. European patent application EP...
  • Oku T, Kayakiri H, Satoh S, Abe Y, Sawada Y, Inoue T, Tanaka H. Pyridopyrimidones, quinolines and fused N-heterocycles...
  • Oku T, Kayakiri H, Satoh S, Abe Y, Sawada Y, Inoue T, Tanaka H. Quinoline derivatives, processes for their preparation,...
  • Abe Y. Discovery of a new class of non-peptide bradykinin B2 receptor antagonists with a novel framework mimicking the...
  • M Asano et al.

    The identification of an orally active nonpeptide bradykinin B2 receptor antagonist, FR173657

    Br J Pharmacol

    (1997)
  • A Rizzi et al.

    FR173657: a new potent nonpeptide kinin B2 receptor antagonist — an in vitro study

    Hypertension

    (1997)
  • I Aramori et al.

    Novel subtype selective nonpeptide bradykinin receptor antagonists FR 167344 and FR 173657

    Mol Pharmacol

    (1997)
  • Meini S, Quartara L, Giolitti A, Maggi CA. MEN 11270, a novel kinin B2 receptor antagonist. The 15th International...
  • Cited by (40)

    • Inflammation in the long arc of history

      2022, Diet, Inflammation, and Health
    • WIN 64338

      2010, xPharm: The Comprehensive Pharmacology Reference
    • Bradykinin

      2007, xPharm: The Comprehensive Pharmacology Reference
    View all citing articles on Scopus
    View full text