Aminoimidazoles as bioisosteres of acylguanidines: novel, potent, selective and orally bioavailable inhibitors of the sodium hydrogen exchanger isoform-1.
Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.
Ahmad
Saleem
S
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. saleem.ahmad@bms.com
Ngu
Khehyong
K
Combs
Donald W
DW
Wu
Shung C
SC
Weinstein
David S
DS
Liu
Wen
W
Chen
Bang-Chi
BC
Chandrasena
Gamini
G
Dorso
Charles R
CR
Kirby
Mark
M
Atwal
Karnail S
KS
D000284:Administration, Oral; D001682:Biological Availability; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D006146:Guanidines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism
D027682:Cation Transport Proteins; D006146:Guanidines; D007093:Imidazoles; D008565:Membrane Proteins; D020033:Protein Isoforms; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers