Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists

5‐HT6 antagonists as potential treatment for cognitive dysfunction

“…Cole showed that 4-piperazinyl-1-sulfonylindoles (e.g., 96) were potent 5-HT 6 antagonists, which further demonstrated the promiscuous nature of the receptor site Cole, 2004, 2006]. This was supported by additional 4-piperazinyl-1-sulfonylindole 5-HT 6 antagonists independently discovered by researchers at GlaxoSmithKline (e.g., 97 and 98) [Ahmed et al, 2005a;Bromidge, 2002], Roche (e.g., 99) [Briggs et al, 2002], and Biovitrum [Caldirola et al, 2002;Johansson et al, 2003]. In addition to excellent affinity, 98 (SB-699929) was also shown to have high selectivity (4100-fold against a range of 50 receptors), good BBB exposure (brain/plasma 5 3), and a suitable PK profile (oral F 5 49% and CL 5 44 mL/min/kg in rats) to warrant additional focus The breadth of structural diversity in this area was also demonstrated by indazoles (e.g., 100) Cole, 2004, 2006] and azaindazoles (e.g., 101), both excellent ligands for the 5-HT 6 receptor [Johansson et al, 2003].…”

“…Workers at GlaxoSmithKline also claimed the 7-piperazinyl-3-sulfonylindole derivatives (e.g., 113) [Bromidge et al, 2003a] in a recent application. 3-Sulfonyl azaindoles with piperazine at the 4-through 7-positions (114-116) were claimed by Wyeth [Bernotas and Yan, 2004] and the 7-piperazinyl azaindole derivatives were also reported more recently by GlaxoSmithKline [Ahmed et al, 2005a]. In addition, Wyeth also reported in a number of applications the 3-sulfonylindazole derivatives with a variety of amines at the 4-through 7-positions as represented by 117-125 [Bernotas et al, 2004b;Elokdah et al, 2007a,b].…”

“…13) Ahmed and coworkers showed that benzofuran (165) and benzothiophene (166) analogs were as potent as their corresponding indole based derivatives [Ahmed et al, 2005a]. Biovitrum claimed a range of benzofuran-and benzothiophene-based derivatives (e.g., 167-172) as potent 5-HT 6 antagonists in several patent applications [Caldirola et al, 2006;Dykes 2006;Johansson et al, 2003Johansson et al, , 2005.…”

Serotonin Receptors of Type 6 (5-HT6): From Neuroscience to Clinical Pharmacology

“…Following this, Ro 65-7199 was found to possess a better lypophilic profile than Ro 04-6790 [74]. Other 5-HT 6 receptor antagonists are the compounds called SB699929 [75,76] [84,85], R-13c [86] have been declared to be 5-HT 6 receptor agonists. ST1936 is a new 5-HT 6 receptor agonist and it has recently been introduced at an international summit [87].…”

5-Hydroxytryptamine (5-HT) Receptor Ligands

“…This compound was shown to be a substrate for the P-glycoprotein (P-gp) efflux pump. This combination was considered to give a high risk of poor brain penetration in humans [64].…”