Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene D4 receptor antagonists. 4. Addition of chromone moiety enhances leukotriene D4 receptor binding affinity

Abstract

The combination of the benzopyran-4-one ring, a moiety found in the prototype leukotriene antagonist, FPL 55,712, with the (2-quinolinylmethoxy)phenyl group led to a significant increase in leukotriene receptor binding affinity. This modification resulted in a 10,000-fold improvement in binding affinity compared to FPL 55,712. Compound 7 (RG 12553), with a Ki value of 0.1 nM, has higher affinity than the natural agonist LTD4 and is one of the most potent LTD4 antagonists reported. The structure-activity relationships of this series of potent leukotriene antagonists are discussed.

Dietary aloin, aloesin, or aloe-gel exerts anti-inflammatory activity in a rat colitis model

“…Zhang et al (1995) reported that the chromone moiety effectively inhibits a LTD4-induced increase in vascular permeability. Huang et al (1991) found that the chromone moiety in the benzopyran-4-one ring led to a significant increase in leukotriene D4 receptor binding affinity. Sener et al (2005) also reported that treatment with a leukotriene receptor antagonist prevented gastrointestinal damage as well as the changes in biochemical parameters in all of the tissues investigated in their study.…”

Chromone: A Valid Scaffold in Medicinal Chemistry

“…In the 1980s and 1990s the discovery and development of novel LT receptor inhibitors based on the chromone nucleus prompted the emergence of pranlukast ( described as LTD4 antagonist [156] (Fig. 2.21).…”

Chromones: A Promising Ring System for New Anti‐inflammatory Drugs

“…[38] Combinationo ft he chromone moiety with the (quinolin-2ylmethoxy)phenyl group led to the discovery of the most potent LT receptora ntagonistr eported so far,R G12553 (21; Figure 11), whichh as even highera ffinity than the natural ligand LTD4 (18;F igure 10). [39] Through SAR studies it was possible to verify that the presence of the chromone moiety itself is not sufficient for high bindinga ffinity.F urthermore,s tructural features like the tetrazole group can be regarded as an acidic function that improves receptor affinity.…”