Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels.
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.
Yang
Zhi-Qiang
ZQ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. zhiqiang_yang@merck.com
Barrow
James C
JC
Shipe
William D
WD
Schlegel
Kelly-Ann S
KA
Shu
Youheng
Y
Yang
F Vivien
FV
Lindsley
Craig W
CW
Rittle
Kenneth E
KE
Bock
Mark G
MG
Hartman
George D
GD
Uebele
Victor N
VN
Nuss
Cindy E
CE
Fox
Steve V
SV
Kraus
Richard L
RL
Doran
Scott M
SM
Connolly
Thomas M
TM
Tang
Cuyue
C
Ballard
Jeanine E
JE
Kuo
Yuhsin
Y
Adarayan
Emily D
ED
Prueksaritanont
Thomayant
T
Zrada
Matthew M
MM
Marino
Michael J
MJ
Graufelds
Valerie Kuzmick
VK
DiLella
Anthony G
AG
Reynolds
Ian J
IJ
Vargas
Hugo M
HM
Bunting
Patricia B
PB
Woltmann
Richard F
RF
Magee
Michael M
MM
Koblan
Kenneth S
KS
Renger
John J
JJ
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
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010880:Piperidines; C032727:piperidine