A commercially available 0.1 M solution of HClO(4) in dioxane has been shown to catalyze the glycosidation of glycosyl diphenyl phosphates. The per-O-benzyl-protected glucosyl and galactosyl donors and the 3,4,6-tri-O-acetyl-2-azido-2-deoxygalactosyl donor each react with a range of acceptor alcohols in the presence of 0.05-0.2 equiv of HClO(4) in dioxane/Et(2)O (1:1) to afford glycosides in good yields with good to excellent alpha selectivities. The synthetic utility of this glycosidation method was demonstrated by a stereoselective synthesis of the alpha-galactosylceramide KRN7000, an activator of natural killer (NK) T cells through CD1d molecules.
A highly
potent, selective NaV1.7 inhibitor, DS-1971a,
has been discovered. Exploration of the left-hand phenyl ring of sulfonamide
derivatives (I and II) led to the discovery
of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic
ring affected the mechanism-based inhibition liability of CYP3A4,
replacement of this moiety resulted in the generation of 4-pyrimidyl
derivatives. Additionally, GSH adducts formation, which can cause
idiosyncratic drug toxicity, was successfully avoided by this modification.
An additional optimization led to the discovery of DS-1971a. In preclinical
studies, DS-1971a demonstrated highly potent selective in vitro profile
with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological
profile, which enabled multiple-dose studies of up to 600 mg bid or
400 mg tid (1200 mg/day) administered for 14 days to healthy human
males. DS-1971a is expected to exert potent efficacy in patients with
peripheral neuropathic pain, with a favorable safety profile.
Leave this area blank for abstract info. Abstract-A direct and practical method for the construction of β-mannosidic linkages is described. While β-selectivities in the TMSOTfpromoted glycosidation of 2,3,4,6-tetra-O-benzyl-D-mannosyl diethyl phosphite are found to be highly dependent on the reactivity of acceptor alcohols, 2,3-di-O-benzyl-4,6-O-benzylidene-D-mannosyl diethyl phosphite reacts with a wide range of acceptor alcohols in the presence of TMSOTf in CH 2 Cl 2 at -45 °C to give β-mannosides in high yields with good to high β-selectivities.
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