title: Discovery of a pharmacologically active antagonist of the two-pore-domain potassium channel K2P9.1 (TASK-3).
abstract: TWIK-related acid-sensitive K(+)  (K(2P) 9.1, TASK-3) ion channels have the capacity to regulate the activity of neuronal pathways by influencing the resting membrane potential of neurons on which they are expressed. The central nervous system (CNS) expression of these channels suggests potential roles in neurologic disorders, and it is believed that the development of TASK-3 antagonists could lead to the therapeutic treatment of a number of neurological conditions. While a therapeutic potential for TASK-3 channel modulation exists, there are only a few documented examples of potent and selective small-molecule channel blockers. Herein, we describe the discovery and lead optimization efforts for a novel series of TASK-3 channel antagonists based on a 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine high-throughput screening lead from which a subseries of potent and selective inhibitors were identified. One compound was profiled in detail with respect to its physical properties and demonstrated pharmacological target engagement as indicated by its ability to modulate sleep architecture in rodent electroencephalogram (EEG) telemetry models.
authors.affiliation: External Medicinal Chemistry, Merck & Co., West Point, PA 19486, USA. craig_coburn@merck.com
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.forename: Yunfu
authors.initials: Y
authors.lastname: Luo
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Cui
authors.forename: Jiabing
authors.initials: J
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Soll
authors.forename: Jingchao
authors.initials: J
authors.lastname: Dong
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lyon
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Santarelli
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kraus
authors.forename: Yun
authors.initials: Y
authors.lastname: Gregan
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Steven V
authors.initials: SV
authors.lastname: Fox
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Binns
authors.forename: Scott M
authors.initials: SM
authors.lastname: Doran
authors.forename: Duane R
authors.initials: DR
authors.lastname: Reiss
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Tannenbaum
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D011743:Pyrimidines; C030986:pyrimidine