2-Substituted 5,6-dimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines: New series of highly potent and specific serotonin 5-HT6 receptor antagonists

Syntheses, biological evaluation, and structure–activity relationships for a series of novel 2-substituted 3-benzenesulfonyl-5,6-dimethyl-pyrazolo[1,5-a]pyrimidines are disclosed. In spite of a wide, four orders of magnitude, SAR range (Ki varied from 260 pM to 2.96 μM), no significant correlation of 5-HT6R antagonistic potency was observed with major physiochemical characteristics, such as molecular weight, surface polar area, cLogP, or number of rotatable bonds. Statistically significant trend was only observed for size of substitute group, which was not enough to explain the deep SAR trend. Besides with the substitute group size, another factor that presumably plays a role in defining the compound potencies is a relative position of the heterocycle and sulfophenyl moieties. Among all synthesized derivatives, (3-benzenesulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 18 is the most potent (Ki = 260 pM) and extremely selective, 5000 to >50,000-fold relative to 55 therapeutic targets, antagonist of the 5-HT6 receptor.

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► Novel 2-substituted 3-benzenesulfonyl-5,6-dimethyl-pyrazolo[1,5-a]pyrimidines.
► The compounds are highly selective 5-HT6 receptors with Ki from 260 pM to 2.96 μM.
► Major physiochemical characteristics are not responsible for the SAR.
► Substitute group size and relative topology of the molecule define the SAR.