- A Rapid Injection NMR Study of the Reaction of Organolithium Reagents with Esters, Amides, and Ketones
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Unexpectedly high rates of reaction between alkyllithium reagents and amides, compared to esters and ketones, were observed by Rapid Inject NMR and competition experiments. Spectroscopic investigations with 4-fluorophenyllithium (ArLi, mixture of monomer and dimer in THF) and a benzoate ester identified two reactive intermediates, a homodimer of the tetrahedral intermediate, stable below -100°C, and a mixed dimer with ArLi. Direct formation of dimers suggested that the ArLi dimer may be the reactive aggregate rather than the usually more reactive monomer. In contrast, RINMR experiments with ketones demonstrated that the ArLi monomer was the reactive species. (Chemical Equation Presented).
- Plessel, Kristin N.,Jones, Amanda C.,Wherritt, Daniel J.,Maksymowicz, Rebecca M.,Poweleit, Eric T.,Reich, Hans J.
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p. 2310 - 2313
(2015/05/27)
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- Novel inhibitors of the gardos channel for the treatment of sickle cell disease
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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
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p. 976 - 982
(2008/12/20)
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- TREATMENT METHODS USING TRIARYL METHANE COMPOUNDS
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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 31
(2008/06/13)
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