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 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.
McNaughton-Smith, Grant A.,Burns, J. Ford,Stocker, Jonathan W.,Rigdon, Gregory C.,Creech, Christopher,Arlington, Susan,Shelton, Tara,De Franceschi, Lucia
p. 976 - 982
(2008/12/20)
TREATMENT METHODS USING TRIARYL METHANE COMPOUNDS
The use of novel inhibitors of potassium flux is disclosed for the treatment of inflammatory processes, such as multiple sclerosis, insulin-dependent (type I) diabetes mellitus, rheumatoid arthritis, peripheral neuritis and pulmonary hypertension. The com
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Page/Page column 27-28
(2008/06/13)
GARDOS CHANNEL ANTAGONISTS
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
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(2008/06/13)
Synthesis and antifungal activity of a series of difluorotritylimidazoles
1-[(2-Fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H-imidazole (flutrimazole, UR-4056, CAS 119006-77-8) (15) was selected among a series of mono-, di- and trifluorotrityl-imidazole antifungal agents as the most potent fluorine containing analogue of clotrimazole.
Bartroli,Alguero,Boncompte,Forn
p. 832 - 835
(2007/10/02)
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