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  • br Conclusion In this report we


    Conclusion In this report, we describe the synthesis and evaluation of oxadiazole-based GSK3 inhibitors. Occupation of the ATP-binding pocket in its entirety led to the identification of several potent and selective compounds. These compounds are characterized by IC50 values in the low nanomolar range and good selectivity versus other kinases. Surprisingly, we ascertained that the addition of different functional groups onto the biphenyl system was adequate to gain selectivity against one GSK-3 isoform. To the best of our knowledge the selectivity of compound 8g for GSK-3α compared to GSK-3β is among the highest ever reported. These observations will be helpful, if the discrimination of one GSK-3 isoform is needed in vivo. The discriminating factor for this isoform selectivity is still unknown as the ATP-binding sites are almost identical in the two isoforms (Fig. 3). Differences in the amino EZ Cap Reagent AG synthesis sequence of the channels leading to the binding sites may hold a cue, but the lack of a crystallized GSK-3α makes this hypothesis highly speculative. Furthermore, amino acids in the second-sphere close to the ATP-binding pocket do vary for GSK-3α and thus may contribute to conformational changes. The interaction with the glycine-rich loop might have significant effects on the binding potencies and selectivities of the biphenyl derivatives similar to the compounds reported by Li Feng et al[22]. The amide function in compound 26d indicated a potential interaction with the backbone exploitable for further improvement. However, this moiety causes a significant contribution to the tPSA (103.0 Å2) and thus impairs potential blood–brain barrier permeation. We exposed wt zebrafish embryos to two of these compounds at early stages of development and obtained desirable in vivo efficacy for compound 9e and 26d. We suppose that GSK-3α inhibition offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles and thus may be valuable in the treatment of AD [51]. On the basis of these results the derivatives 8b, 8g and 26d were selected for further pharmacological and structural evaluations.
    Introduction GSK-3 is a kinase that phosphorylates numerous substrates on serine (S) and threonine (T) residues. For GSK-3 to phosphorylate its substrates efficiently, many substrates are first phosphorylated by casein kinase I (CKI) and other kinases depending upon the particular substrate protein. This is referred to as a priming phosphorylation event. GSK-3 was initially identified in rat skeletal muscle as an enzyme EZ Cap Reagent AG synthesis that phosphorylated and inactivated glycogen synthase (GS), the last enzyme in glycogen biosynthesis [1], [2]. Thus, initially GSK-3 was thought to have key roles in metabolism but this characteristic is only the tip of the iceberg in terms of the diverse activities of the GSK-3 moonlighting enzyme [3], [4], [5], [6], [7]. At least forty GSK-3 substrates have been identified [7]. GSK-3 is a gene family consisting of GSK-3alpha (51kDa) and GSK-3beta (47kDa) [8], [9]. While these two GSK-3 family members have many conserved biochemical functions, they also have unique activities and different substrates in neurological and other tissues [8], [9], [10], [11]. GSK-3beta knock-out mice are embryonically-lethal indicating that wild type (WT) GSK-3alpha cannot fully compensate for GSK-3beta. GSK-3alpha mice are not embryonically-lethal but they have defects in metabolism and reduced fat mass [9]. GSK-3alpha knockout mice have enhanced glucose and insulin sensitivity and neuronal developmental abnormalities [10]. Most studies have focused on GSK-3beta, however, more recent studies are indicating unique roles for GSK-3alpha and it may play prominent roles in certain cancer stem cells (CSCs) [11], [12]. Over the years, GSK-3 has been shown to be important in many physiological processes. GSK-3 has critical functions in many diseases and disorders including: metabolic disorders (diabetes, atherosclerosis, and heart disease) [13], [14], [15], [16], neurological disorders (Parkinson's, Alzheimer's, amyotrophic lateral sclerosis [ALS], schizophrenia, bipolar disorder, and mood disorders) [17], [18] and more recently, cancer and aging (cellular senescence, cancer stem cells [CSC], resistance to chemotherapy, radiotherapy and targeted therapy [19], [20], [21], control of stem cell pluripotency and differentiation) [22], [23], [24], immune disorders and other maladies [25], [26], [27], [28], [29], [30], [31]. GSK-3 is a target of lithium that for decades has been used in the treatment of patients suffering from bipolar and mood disorders [28]. Recent studies indicate that GSK-3 may be a therapeutic target for certain cancers and immunological and other diseases [12], [30], [31].