N-Desbutyl dronedarone is an active metabolite of the antiarrhythmic agent dronedarone .1,2,3It is formed from dronedarone by cytochrome P450s (CYPs) and monoamine oxidase (MAO) in human hepatocyte preparations.4N-Desbutyl dronedarone inhibits the binding of 3,3’,5-triiodo-L-thyronine to the thyroid hormone receptors TRα1and TRβ1(IC50s = 59 and 280 μM for the chicken and human receptors, respectively).1It inhibits CYP2J2-mediated formation of 14,15-EET from arachidonic acid and soluble epoxide hydrolase-mediated formation of 14,15-DHET from 14,15-EET (IC50s = 1.59 and 2.73 μM, respectively, in cell-free assays).2N-Desbutyl dronedarone decreases intracellular ATP levels in H9c2 rat cardiomyocytes (IC50= 1.07 μM) and inhibits mitochondrial complex I, also known as NADH dehydrogenase, and mitochondrial complex II, also known as succinate dehydrogenase, activities in isolated rat heart mitochondria (IC50s = 11.94 and 24.54 μM, respectively).3 1.Van Beeren, H.C., Jong, W.M.C., Kaptein, E., et al.Dronerarone acts as a selective inhibitor of 3,5,3’-triiodothyronine binding to thyroid hormone receptor-α1: in vitro and in vivo evidenceEndocrinology144(2)552-558(2003) 2.Karkhanis, A., Tram, N.D.T., and Chan, E.C.Y.Effects of dronedarone, amiodarone and their active metabolites on sequential metabolism of arachidonic acid to epoxyeicosatrienoic and dihydroxyeicosatrienoic acidsBiochem. Pharmacol.146188-198(2017) 3.Karkhanis, A., Leow, J.W.H., Hagen, T., et al.Dronedarone-induced cardiac mitochondrial dysfunction and its mitigation by epoxyeicosatrienoic acidsToxicol. Sci.163(1)79-91(2018) 4.Klieber, S., Arabeyre-Fabre, C., Moliner, P., et al.Identification of metabolic pathways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drugPharmacol. Res. Perspec.2(3)e00044(2014)
S-Nitrosothiols (RSNOs) are a class of molecules that function as exogenous and endogenous nitric oxide (NO) donors. RSNOs found in vivo include proteins such as S-nitrosohemoglobin and S-nitrosoalbumin, as well as low molecular weight species such as S-nitrosoglutathione (GSNO) and S-nitrosocysteine (CysNO). CAY10563 is a member of a new class of S-nitrosothiol species that act as an NO donors under acidic conditions. It decomposes with a half-life of one minute in 0.1 M phosphate buffer, pH 5.0, at 37°C and relaxes phenylephrine-constricted rat aortic strips 59% and 16% at pH 6.0 and 7.4, respectively.
S-Nitrosothiols (RSNOs) are a class of molecules that function as exogenous and endogenous nitric oxide (NO) donors. RSNOs found in vivo include proteins such as S-nitrosohemoglobin and S-nitrosoalbumin, as well as low molecular weight species such as S-nitrosoglutathione (GSNO) and S-nitrosocysteine (CysNO). CAY10564 is a member of a new class of S-nitrosothiol species that act as NO donors under acidic conditions. It decomposes with a half-life of one minute in 0.1 M phosphate buffer, pH 5.0, at 37°C and relaxes phenylephrine-constricted rat aortic strips 59% and 16% at pH 6.0 and 7.4, respectively.
EBI-907 is a highly potent and orally efficacious B-RafV600E inhibitor. EBI-907 displays a low single-digit nanomolar activity (IC50 = 4.9 nM), which is >10-fold more potent than Vemurafenib (IC50 = 59 nM). EBI-907 also exhibits high potency in selectively inhibiting the proliferation of BRAF (V600E)-dependent cell lines (A375 and Colo205) and cellular Erk phosporylation, with superior activity to Vemurafenib. EBI-907, displaying potent activity against a number of important oncogenic kinases including BRK, FGFR1, c-Kit, and PDGFRb.