N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as Potent and Selective Inhibitors of Glycogen Synthase Kinase 3 with Good Cellular Efficacy

Abstract

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.

Facile microwave-assisted synthesis of bis-pyrazol pyrimidine derivatives via an N-alkylation reaction

“…Derivatives of pyrazol pyrimidine have also been reported as promising pharmaceutical agents for treatment of cancer [5], neurodegenerative diseases [6], diabetes [7], and inflammation [8,9]. Among these compounds, an increasing number of 4-(pyrazol-4-yl)pyrimidines have been used to generate inhibitors of various kinases including Aurora kinases, N-terminal kinases, p38 MAPK, and Raf kinases [5,[10][11][12][13].…”

Synthesis, crystal structures, and biological activities of silver(I) and cobalt(II) complexes with an azole derivative ligand

“…Azole derivatives are widely applied to the synthesis of pesticides [1] and medicines because of their notable biological activities [2,3]. Azoles are also used in the realm of coordinated functional materials [4][5][6][7], where they act as good electron donors and also provide weak interactions, such as p-p interactions, hydrogen bonds, and C-HÁÁÁp interactions, by which higher dimensional coordinated polymers can be assembled [8].…”

A 2D image-based approach for modelling some glycogen synthase kinase 3 inhibitors

“…GSK-3 inhibitors are widely used as therapeutic agents against diabetes (Castro and Martinez, 2000), stroke, cancer, and other maladies (Hoeflich et al, 2000). Thus, the synthesis and prediction of novel GSK-3 inhibitors has been subject of a variety of studies (Engler et al, 2005;Cross et al, 2001;Hers et al, 1999;Kuo et al, 2003;Leost et al, 2000;Meijer et al, 2000;Meijer et al, 2003;Peat et al, 2004;Ring et al, 2003;Tavares et al, 2004). recently designed a series of GSK-3 ligands using a de novo approach, whose docking methodology was calibrated using a series of reference compounds.…”

“…Alternatively, multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) appeared as an approach to circumvent such problems, since it avoids 3D treatments (Freitas et al, 2005;Freitas, 2006). This method was applied here to model a series of 17 GSK-3 inhibitors obtained from literature (Engler et al, 2005;Cross et al, 2001;Hers et al, 1999;Kuo et al, 2003;Leost et al, 2000;Meijer et al, 2000;Meijer et al, 2003;Peat et al, 2004;Ring et al, 2003;Tavares et al, 2004), and its potentialities discussed.…”