ReviewNonpeptide antagonists for kinin receptors
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
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