title: 2-Substituted 5,6-dimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines: new series of highly potent and specific serotonin 5-HT6 receptor antagonists.
abstract: 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 (K(i) varied from 260 pM to 2.96 μM), no significant correlation of 5-HT(6)R 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 (K(i) = 260 pM) and extremely selective, 5000 to >50,000-fold relative to 55 therapeutic targets, antagonist of the 5-HT(6) receptor.
authors.affiliation: Department of Organic Chemistry, Chemical Diversity Research Institute, 141400 Khimki, Moscow Reg, Russia.
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Ivachtchenko
authors.forename: Elena S
authors.initials: ES
authors.lastname: Golovina
authors.forename: Madina G
authors.initials: MG
authors.lastname: Kadieva
authors.forename: Angela G
authors.initials: AG
authors.lastname: Koryakova
authors.forename: Oleg D
authors.initials: OD
authors.lastname: Mitkin
authors.forename: Sergey E
authors.initials: SE
authors.lastname: Tkachenko
authors.forename: Volodymyr M
authors.initials: VM
authors.lastname: Kysil
authors.forename: Ilya
authors.initials: I
authors.lastname: Okun
mesh_terms: D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013379:Substrate Specificity; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013450:Sulfones; C097216:serotonin 6 receptor