Design, synthesis, and evaluation of a novel 4-aminomethyl-4-fluoropiperidine as a T-type Ca2+ channel antagonist.
The novel T-type antagonist ( S)- 5 has been prepared and evaluated in in vitro and in vivo assays for T-type calcium ion channel activity. Structural modification of the piperidine leads 1 and 2 afforded the fluorinated piperidine ( S)- 5, a potent and selective antagonist that displayed in vivo CNS efficacy without adverse cardiovascular effects.
Department of Medicinal Chemistry, Merck Research Laboratories, WP14-1, P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, USA. william_shipe@merck.com
William D
WD
Shipe
James C
JC
Barrow
Zhi-Qiang
ZQ
Yang
Craig W
CW
Lindsley
F Vivien
FV
Yang
Kelly-Ann S
KA
Schlegel
Youheng
Y
Shu
Kenneth E
KE
Rittle
Mark G
MG
Bock
George D
GD
Hartman
Cuyue
C
Tang
Jeanine E
JE
Ballard
Yuhsin
Y
Kuo
Emily D
ED
Adarayan
Thomayant
T
Prueksaritanont
Matthew M
MM
Zrada
Victor N
VN
Uebele
Cindy E
CE
Nuss
Thomas M
TM
Connolly
Scott M
SM
Doran
Steven V
SV
Fox
Richard L
RL
Kraus
Michael J
MJ
Marino
Valerie Kuzmick
VK
Graufelds
Hugo M
HM
Vargas
Patricia B
PB
Bunting
Martha
M
Hasbun-Manning
Rose M
RM
Evans
Kenneth S
KS
Koblan
John J
JJ
Renger
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D000882:Haplorhini; D006339:Heart Rate / Q000187:drug effects; D023421:Models, Animal; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010880:Piperidines; D011714:Pyrans