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Gardos channel antagonists

A technology of excipients and substituents, applied in the field of fluorine-substituted triarylmethane-based inhibitors, can solve the problems of low bioavailability, low efficacy of Gardos channel inhibitors, high doses, etc.

Inactive Publication Date: 2005-03-23
ICAGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Another disadvantage of many known Gardos channel inhibitors is that their interaction with calcium-activated potassium channels is not specific: these drugs tend to react with other calcium-activated potassium channels that are not Gardos channels
In summary, the low potency, specificity, and low bioavailability of known Gardos channel inhibitors necessitate higher doses and more frequent dosing, increasing the risk of adverse side effects and toxicity

Method used

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  • Gardos channel antagonists
  • Gardos channel antagonists
  • Gardos channel antagonists

Examples

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Embodiment 1

[0157]Example 1 illustrates the synthesis and characterization of compounds of the invention. The compounds of the invention can be isolated in substantially pure form and in good yields using the procedures detailed in this example.

Embodiment 2

[0158] Example 2 illustrates the analysis of the resistance of compounds of the invention to degradation in biological media. In this example, human liver microsomes were used to form the biomedia. It was found that the compounds of the invention exhibited significant resistance to degradation by microsomal preparations relative to non-fluorinated tritylmethyl compounds.

Embodiment 3

[0159] Example 3 sets forth the pharmacokinetic studies performed on the compounds of the invention in rats. It was found that the fluorinated compounds of the present invention exhibit an increased half-life in vivo relative to the non-fluorinated derivatives.

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Abstract

Novel inhibitors of potassium flux are disclosed. The inhibitors show surprising resistance to degradation in biological media and enhanced in vivo half-lives relative to non-fluorine substituted homologues. Methods for the use of these compounds include treating sickle cell disease, preventing erythrocyte dehydration and inhibiting potassium flux.

Description

[0001] Cross-references to related applications [0002] This application claims priority to U.S. Provisional Application No. 60 / 135,511, filed March 24, 1999, the contents of which are incorporated herein by reference in their entirety. field of invention [0003] The present invention relates to erythrocyte Ca 2+ - Organic compounds that are specific, potent and safe inhibitors of activated potassium channels (Gardos channels). In particular, the present invention relates to fluorine-substituted triarylmethane inhibitors which exhibit significantly improved resistance against degradation in in vitro biological media and exhibit extended half-lives relative to their non-fluorinated congeners. Background of the invention [0004] Sickle cell disease has been found in West Africa for centuries. Sickle cell anemia and the presence of sickle hemoglobin (Hb S) were the first genetic disorders recognized at the molecular level. Its morphological and clinical consequences are n...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/165C07C233/11
CPCC07C233/11A61K31/165A61P43/00A61P7/00C07C233/65
Inventor G·A·麦克诺顿-史密斯G·C·里格登J·W·施特克尔
Owner ICAGEN INC