title: Synthesis and SAR of 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines as potent serotonin 5-HT6 receptor antagonists.
abstract: Syntheses of a series of novel 3-sulfonyl-pyrazolo[1,5-a]pyrimidines and their 5-HT(6) receptor antagonistic structure-activity relationship are disclosed. The nature and position of substituents, which affect their receptor antagonistic activity, are analyzed. Among all synthesized derivatives, {3-(3-chlorophenylsulfonyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl}-methyl-amine 33 (K(i)=190 pM), (3-phenylsulfonyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 44 (K(i)=240 pM), (3-phenylsulfonyl-5-metoxymethyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 50 (K(i)=270 pM), and (3-phenylsulfonyl-5-methyl-7-metoxymethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 52 (K(i)=280 pM) are the most potent antagonists of the 5-HT(6) receptors.
authors.affiliation: Department of Organic Chemistry, Chemical Diversity Research Institute, 141401 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: Volodymyr M
authors.initials: VM
authors.lastname: Kysil
authors.forename: Oleg D
authors.initials: OD
authors.lastname: Mitkin
authors.forename: Sergey E
authors.initials: SE
authors.lastname: Tkachenko
authors.forename: Ilya
authors.initials: I
authors.lastname: Okun
mesh_terms: D002460:Cell Line; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000737:chemistry
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D011720:Pyrazoles; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013457:Sulfur Compounds; C097216:serotonin 6 receptor; C031280:pyrazole; C030986:pyrimidine