Novel Inhibitors of the Gardos Channel for the Treatment of Sickle Cell Disease

Sickle cell disease (SCD) is a hereditary condition characterized by deformation of red blood cells (RBCs). This phenomenon is due to the presence of abnormal hemoglobin that polymerizes upon deoxygenation. This effect is exacerbated when dehydrated RBCs experience a loss of both water and potassium...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-02, Vol.51 (4), p.976-982
Main Authors: McNaughton-Smith, Grant A, Burns, J. Ford, Stocker, Jonathan W, Rigdon, Gregory C, Creech, Christopher, Arrington, Susan, Shelton, Tara, de Franceschi, Lucia
Format: Article
Language:English
Subjects:
Acetamides - chemical synthesis
Acetamides - pharmacokinetics
Acetamides - pharmacology
Anemia, Sickle Cell - drug therapy
Animals
Biological and medical sciences
Biological Availability
Blood. Blood coagulation. Reticuloendothelial system
Clotrimazole - pharmacokinetics
Clotrimazole - pharmacology
Humans
Intermediate-Conductance Calcium-Activated Potassium Channels - physiology
Male
Medical sciences
Mice
Pharmacology. Drug treatments
Potassium Channel Blockers - chemical synthesis
Potassium Channel Blockers - pharmacokinetics
Potassium Channel Blockers - pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Trityl Compounds - chemical synthesis
Trityl Compounds - pharmacokinetics
Trityl Compounds - pharmacology
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Summary:Sickle cell disease (SCD) is a hereditary condition characterized by deformation of red blood cells (RBCs). This phenomenon is due to the presence of abnormal hemoglobin that polymerizes upon deoxygenation. This effect is exacerbated when dehydrated RBCs experience a loss of both water and potassium salts. One critical pathway for the regulation of potassium efflux from RBCs is the Gardos channel, a calcium-activated potassium channel. This paper describes the synthesis and biological evaluation of a series of potent inhibitors of the Gardos channel. The goal was to identify compounds that were potent and selective inhibitors of the channel but had improved pharmacokinetic properties compared to 1, Clotrimazole. Several triarylamides such as 10 and 21 were potent inhibitors of the Gardos channel (IC50 of
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070663s