Article ID Journal Published Year Pages File Type
10596587 Bioorganic & Medicinal Chemistry Letters 2012 8 Pages PDF
Abstract
Synthesis and biological evaluation of a new series of structurally unrestricted and intramolecular hydrogen bond restricted derivatives of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines (angular tricyclics) and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines (linear tricyclics) are described. Structurally restricted derivatives are highly potent and selective blockers of 5-HT6 receptors with little difference between angular or linear shape of the tricyclic core, the angular species being only slightly more potent. The angular representative of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines, 5, can be considered as more favorable candidate for further development as it shows only weak 5-HT2B blocking activity (IC50 = 6.16 μM as compared with IC50 = 1.8 nM for 5-HT6 receptors) and very low hERG potassium channel blocking potency (IC50 = 54.2 μM). The linear analog, 11, is less favorable as while showing no binding to the 5-HT2B receptor at concentrations of up to 10 μM, it exhibits quite a high potency to block the hERG channel (IC50 = 0.5 μM).
Related Topics
Physical Sciences and Engineering Chemistry Organic Chemistry
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