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 Myocardia

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• 作者：John D. Huber ; J枚rg Bentzien ; Stephen J. Boyer ; Jennifer Burke ; St茅phane 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 23, 2012
• 年：2012
• 卷：55
• 期：16
• 页码：7114-7140
• 全文大小：765K
• 年卷期：v.55,no.16(August 23, 2012)
• ISSN：1520-4804

文摘

Sodium鈥揾ydrogen 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鈥揹rug 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.