Identification of a potent sodium hydrogen exchanger isoform 1 (NHE1) inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat.
Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877, United States. john.huber@boehringeringelheim.com
John D
JD
Huber
Jörg
J
Bentzien
Stephen J
SJ
Boyer
Jennifer
J
Burke
Stéphane
S
De Lombaert
Christian
C
Eickmeier
Xin
X
Guo
James V
JV
Haist
Eugene R
ER
Hickey
Paul
P
Kaplita
Morris
M
Karmazyn
Raymond
R
Kemper
Charles A
CA
Kennedy
Thomas
T
Kirrane
Jeffrey B
JB
Madwed
Elizabeth
E
Mainolfi
Nelamangara
N
Nagaraja
Fariba
F
Soleymanzadeh
Alan
A
Swinamer
Anne B
AB
Eldrup
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D002463:Cell Membrane Permeability; D048429:Cell Size; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D008567:Membranes, Artificial; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010539:Permeability; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001549:Benzamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006146:Guanidines; D008567:Membranes, Artificial; C576401:N-(4-(1-acetyl-piperidin-4-yl)-3-trifluoromethylbenzoyl)guanidine; D020033:Protein Isoforms; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers