Original article 2-Substituted 5,6-dimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines: New series of highly potent and specific serotonin 5-HT 6 receptor antagonists Alexandre V. Ivachtchenko a, b , Elena S. Golovina c , Madina G. Kadieva a , Angela G. Koryakova c , Oleg D. Mitkin a , Sergey E. Tkachenko b , Volodymyr M. Kysil b , Ilya Okun b, * a Department of Organic Chemistry, Chemical Diversity Research Institute,141400 Khimki, Moscow Reg, Russia b ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121, USA c Department of Molecular Pharmacology, Chemical Diversity Research Institute,141400 Khimki, Moscow Reg, Russia article info Article history: Received 31 July 2010 Received in revised form 24 January 2011 Accepted 25 January 2011 Available online 1 February 2011 Keywords: Phenylsulfonyl Pyrazolopyrimidine 5-HT 6 receptor antagonist SAR abstract Syntheses, biological evaluation, and structureeactivity 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 mM), 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 ¼ 260 pM) and extremely selective, 5000 to >50,000-fold relative to 55 therapeutic targets, antag- onist of the 5-HT 6 receptor. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Serotonin 5-HT 6 receptors (5-HT 6 R) have attracted considerable interest [1] due to high affinity to a wide range of psychiatric drugs and its specific distribution in the brain. Development of highly potent and selective antagonists would help clarifying the role of the 5-HT 6 R in brain functions as well as in etiology of the central neural system (CNS) diseases. At present, there are only few selective antagonists that have been developed and which have progressed to Phase I and Phase II clinical trials as potential drugs for treatment of various CNS diseases [2e7]. Recently, we have reported [8,9] on the synthesis and biological activity of novel 5-HT 6 R antagonists, 3-phenylsulfonyl-cycloalkano [e and d]pyrazolo[1,5-a]pyrimidines I and II (Fig. 1), which posses both the picomolar range affinity and excellent selectivity profiles. Unlike Ro-65-7674, the new highly potent and selective 5-HT 6 R antagonists I and II either did not possess a positive ionizable group (PI) at all [8] or the PI was located in R 1 position [9]. Though in accordance with the pharmacophore model suggested based on analyses of 45 structurally diverse 5-HT 6 R antagonists, PI was considered as an essential recognition group [10] our data indicated that it might not be necessary determinant of the high antagonist affinity. We have suggested [9] that R 1 substitute group likely served to constrain the phenylsulfo moiety in an appropriate conformation that affected the binding affinity. 2. Chemistry In this paper, we attempted to evaluate the role of the R 1 substituent group in defining the 5-HT 6 R antagonistic activity compounds. We have synthesized a series of new substituted 5,7- dimethyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidines (DMPSPP) 13e23 (Scheme 1) and assessed their serotonin 5-HT 6 R activity. The DMPSPPs 13e23 were synthesized by cyclocondensation of 3-ami- nopyrazoles 1e 11 with acetylacetone 12 in high yields (Scheme 1). In addition, 2-{[5,7-dimethyl-3-(phenylsulfonyl)pyrazolo[1,5-a] pyrimidin-2-yl]oxy}-N,N-dimethylethanamine 24 (Scheme 2) was synthesized in 60% yield by one-pot procedure starting from alcohol 15 that reacted with trifluoromethylsulfonic acid anhydride Abbreviations: 5-HT 6 R, serotonin 5-HT 6 receptor; 5-HT 2B R, serotonin 5-HT 2B receptor; DMPSPP, 5,7-dimethyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine; TPSA, topological polar surface area; CNS, central neural system; PI, positive ionizable group; DMEM, Dulbecco’s Modified Eagle’s Medium; FBS, fetal bovine serum; HBSS, Hank’s balanced salt solution; IBMX, 1-methyl-3-isobutylxanthine. * Corresponding author. Tel.: þ1 858 974 4860; fax: þ1 858 794 4931. E-mail address: iokun@chemdiv.com (I. Okun). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.01.038 European Journal of Medicinal Chemistry 46 (2011) 1189e1197