CGP57698: A Structurally Simple, Highly Potent Peptidoleukotriene (PLT) Antagonist of the Quinoline Type

Sprecher, Andreas von; Gerspacher, Marc; Beck, Andreas; Anderson, Gary P.; Niederhauser, U; Subramanian, N.; Ball, Howard; Gentsch, C.; Vassout, A.; Felner, Aina E.; Bittiger, H.; Hauser, Kathleen; Giese, Karl-Peter; Kraetz, J.; Bray, M.A.

doi:10.1007/978-1-4899-1810-9_34

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“…As far as iralukast is concerned, no augmentative antagonism is apparent. However, in the guinea‐pig tracheal and lung strip preparations, iralukast clearly exhibits an apparent noncompetitive antagonism to LTD 4 challenge (Bray et al , 1990), whilst CGP 57698 is a full competitive antagonist of LTD 4 ‐induced guinea‐pig tracheal contractions (von Sprecher et al , 1996; 1997; and Bray, personal communication).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological characterization of the cysteinyl‐leukotriene antagonists CGP 45715A (iralukast) and CGP 57698 in human airways in vitro

Capra¹,

Bolla²,

Belloni³

et al. 1998

British J Pharmacology

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1 Cysteinyl-leukotrienes (cysteinyl-LTs) are important mediators in the pathogenesis of asthma. They cause bronchoconstriction, mucus hypersecretion, increase in microvascular permeability, plasma extravasation and eosinophil recruitment. 2 We investigated the pharmacological pro®le of the cysteinyl-LT antagonists CGP 45715A (iralukast), a structural analogue of LTD 4 and CGP 57698, a quinoline type antagonist, in human airways in vitro, by performing binding studies on human lung parenchyma membranes and functional studies on human isolated bronchial strips. 3 Competition curves vs [ 3 H]-LTD 4 on human lung parenchyma membranes demonstrated that: (a) both antagonists were able to compete for the two sites labelled by [ 3 H]-LTD 4 ; (b) as in all the G-protein coupled receptors, iralukast and CGP 57698 did not discriminate between the high and the low a nity states of the CysLT receptor labelled by LTD 4 (K i1 =K i2 =16.6 nM+36% CV and K i1 = K i2 =5.7 nM+19% CV, respectively); (c) iralukast, but not CGP 57698, displayed a slow binding kinetic, because preincubation (15 min) increased its antagonist potency. 4 In functional studies: (a) iralukast and CGP 57698 antagonized LTD 4 -induced contraction of human bronchi, with pA 2 values of 7.77+4.3% CV and 8.51+1.6% CV, respectively, and slopes not signi®cantly di erent from unity; (b) the maximal LTD 4 response in the presence of CGP 57698 was actually increased, thus clearly deviating from apparent simple competition. 5 Both antagonists signi®cantly inhibited antigen-induced contraction of human isolated bronchial strips in a concentration-dependent manner, lowering the upper plateau of the anti-IgE curves. 6 In conclusion, the results of the present in vitro investigation indicate that iralukast and CGP 57698 are potent antagonists of LTD 4 in human airways, with a nities in the nanomolar range, similar to those obtained for ICI 204,219 and ONO 1078, two of the most clinically advanced CysLT receptor antagonists. Thus, these compounds might be useful drugs for the therapy of asthma and other allergic diseases.

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Section: Discussionmentioning

confidence: 99%

“…Iralukast and CGP 57698 are two recently developed potent cysteinyl‐LT antagonists that have been shown to be active in various animal models, both in vitro and in vivo (Bray et al , 1990; von Sprecher et al , 1991a,b; 1996; 1997).…”

Section: Introductionmentioning

confidence: 99%