Novel inhibitors of the Gardos channel for the treatment of sickle cell disease.

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McNaughton-Smith GA, Burns JF, Stocker JW, Rigdon GC, Creech C, Arrington S, Shelton T, de Franceschi L

Novel inhibitors of the Gardos channel for the treatment of sickle cell disease.

J Med Chem. 2008 Feb 28;51(4):976-82. doi: 10.1021/jm070663s. Epub 2008 Jan 31.

PubMed ID

18232633 [ View in PubMed

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Abstract

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 <10 nM) and active in a mouse model of SCD. Compound 21 (ICA-17043) was advanced into phase 3 clinical trials for SCD.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Clotrimazole	Intermediate conductance calcium-activated potassium channel protein 4	IC 50 (nM)	360	N/A	N/A	Details