Antagonists of 5-HT6 receptors. Substituted 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines—Synthesis and ‘structure–activity’ relationship

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-HT 6 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-HT 2B blocking activity (IC 50  = 6.16 μM as compared with IC 50  = 1.8 nM for 5-HT 6 receptors) and very low hERG potassium channel blocking potency (IC 50  = 54.2 μM). The linear analog, 11 , is less favorable as while showing no binding to the 5-HT 2B receptor at concentrations of up to 10 μM, it exhibits quite a high potency to block the hERG channel (IC 50  = 0.5 μM).