Discovery of zoniporide: a potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility.
Zoniporide (CP-597,396) is a potent and selective inhibitor of NHE-1, which exhibits high aqueous solubility and acceptable pharmacokinetics for intravenous administration. The discovery, synthesis, activities, and rat and dog pharmacokinetics of this compound are presented. The potency and selectivity of zoniporide may be due to the conformation that the molecule adopts due to the presence of a cyclopropyl and a 5-quinolinyl substituent on the central pyrazole ring of the molecule.
Pfizer Global Research and Development, Pfizer Inc., Groton CT 06340, USA. angel_guzman-perez@groton.pfizer.com
A
A
Guzman-Perez
R T
RT
Wester
M C
MC
Allen
J A
JA
Brown
A R
AR
Buchholz
E R
ER
Cook
W W
WW
Day
E S
ES
Hamanaka
S P
SP
Kennedy
D R
DR
Knight
P J
PJ
Kowalczyk
R B
RB
Marala
C J
CJ
Mularski
W A
WA
Novomisle
R B
RB
Ruggeri
W R
WR
Tracey
R J
RJ
Hill
D000818:Animals; D004285:Dogs; D006146:Guanidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D008968:Molecular Conformation; D020011:Protective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000737:chemistry
D006146:Guanidines; D020011:Protective Agents; D011720:Pyrazoles; C513110:Slc9a2 protein, rat; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D014867:Water; C424422:zoniporide