Document Detail


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.
MedLine Citation:
PMID:  22803959     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
John David Huber; Jörg Bentzien; Stephen J Boyer; Jennifer Burke; Stéphane De Lombaert; Christian Eickmeier; Xin Guo; James V Haist; Eugene R Hickey; Paul Kaplita; Morris Karmazyn; Raymond Kemper; Charles A Kennedy; Thomas Kirrane; Jeffrey B Madwed; Elizabeth Mainolfi; Nelamangara Nagaraja; Fariba Soleymanzadeh; Alan Swinamer; Anne B Eldrup
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-17
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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