- AMIDO-BENZYL SULFONE AND SULFONAMIDE DERIVATIVES
-
Disclosed are certain amido-benzyl sulfone and sulfonamide compounds, pharmaceutical compositions comprising such compounds, land methods of treatment using such compounds.
- -
-
Page/Page column 99
(2013/09/12)
-
- N-phenyl-4-pyrazolo[1,5-6]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy
-
Glycogen synthase kinase 3 regulates glycogen synthase, the rate-determining enzyme for glycogen synthesis. Liver and muscle glycogen synthesis is defective in type 2 diabetics, resulting in elevated plasma glucose levels. Inhibition of GSK-3 could potentially be an effective method to control plasma glucose levels in type 2 diabetics. Structure-activity studies on a N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine series have led to the identification of potent and selective compounds with good cellular efficacy. Molecular modeling studies have given insights into the mode of binding of these inhibitors. Since the initial leads were also potent inhibitors of CDK-2/CDK-4, an extensive SAR was performed at various positions of the pyrazolo[1,5-b] pyridazin core to afford potent GSK-3 inhibitors that were highly selective over CDK-2. In addition, these inhibitors also exhibited very good cell efficacy and functional response. A representative example was shown to have good oral exposure levels, extending their utility in an in vivo setting. These inhibitors provide a viable lead series in the discovery of new therapies for the treatment of type 2 diabetes.
- Tavares, Francis X.,Boucheron, Joyce A.,Dickerson, Scott H.,Griffin, Robert J.,Preugschat, Frank,Thomso, Stephen A.,Wang, Tony Y.,Zhouf, Hui-Qiang
-
p. 4716 - 4730
(2007/10/03)
-
- A short and efficient synthesis of 3,4-dialkoxypyrroles
-
3,4-Dialkoxypyrroles are obtained in four steps from commercially available 2,5-dimethoxy-2,5-dihydrofuran (1). The dihydrofuran 1 is first oxidized by KMnO4 to the diol 2 which is bis-alkylated to 3a-d. Reaction of the in situ generated dialdehydes with a primary amine affords the N- substituted dialkoxypyrroles 4a-m. N-Benzyl-3,4-dialkoxypyrroles and N- allyl-dialkoxypyrroles are cleaved by sodium in liquid ammonia affording N- unsubstituted dialkoxypyrroles 5a-c in good overall yield.
- Merz, Andreas,Meyer, Thomas
-
-
