title: Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels.
abstract: The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 microM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. zhiqiang_yang@merck.com
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yang
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: William D
authors.initials: WD
authors.lastname: Shipe
authors.forename: Kelly-Ann S
authors.initials: KA
authors.lastname: Schlegel
authors.forename: Youheng
authors.initials: Y
authors.lastname: Shu
authors.forename: F Vivien
authors.initials: FV
authors.lastname: Yang
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Rittle
authors.forename: Mark G
authors.initials: MG
authors.lastname: Bock
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.forename: Cindy E
authors.initials: CE
authors.lastname: Nuss
authors.forename: Steve V
authors.initials: SV
authors.lastname: Fox
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kraus
authors.forename: Scott M
authors.initials: SM
authors.lastname: Doran
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Connolly
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
authors.forename: Jeanine E
authors.initials: JE
authors.lastname: Ballard
authors.forename: Yuhsin
authors.initials: Y
authors.lastname: Kuo
authors.forename: Emily D
authors.initials: ED
authors.lastname: Adarayan
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Zrada
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marino
authors.forename: Valerie Kuzmick
authors.initials: VK
authors.lastname: Graufelds
authors.forename: Anthony G
authors.initials: AG
authors.lastname: DiLella
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Reynolds
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Bunting
authors.forename: Richard F
authors.initials: RF
authors.lastname: Woltmann
authors.forename: Michael M
authors.initials: MM
authors.lastname: Magee
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Koblan
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002319:Cardiovascular System / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010880:Piperidines; C032727:piperidine