Glycogen synthase kinase-3 inhibitors
AssigneeTel Aviv University Future Technology Development L.P.
InventorsHagit Eldar-Finkelman, Moshe Portnoy
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Abstract
Novel compounds designed to allow interactions with binding sites of GSK-3 and hence are capable of inhibiting GSK-3 activity, via inhibition of substrate binding are disclosed. Further disclosed are pharmaceutical compositions including same and methods of using same in the treatment of GSK-3 mediated conditions.
Claims54
A compound comprising a negatively charged group and at least one amino moiety-containing group being covalently linked therebetween via a spacer, said spacer having a length, structure and flexibility selected for allowing at least one interaction between said negatively charged group and a first binding site in a catalytic domain of a GSK-3 and at least one interaction between said amino moiety-containing group and a second binding site in said catalytic domain of a GSK-3, such that the compound is capable of inhibiting a catalytic activity of a GSK-3,
- with the proviso that the compound is not selected from the group consisting of compounds having a general formula A or B:
- wherein, for Formula A:
- M is methylene or absent;
- Ra, Rb and T are each hydrogen;
- and
- Rc and Rd are each independently selected from the group consisting of hydrogen, —CH═N—NH—C(═NH)—NH2, —CH2—N(NH2)—CH3 and —CH2—NH—C(═NH)—OH, and
- for Formula B:
- M is methylene or absent;
- Z and W are each independently nitrogen or carbon, at least one of Z and W being nitrogen;
- and
- Re, Rf, Rg, Rh and T are each independently selected from the group consisting of hydrogen, nitro, alkyl, halo, hydroxy and methyl.
A method of inhibiting an activity of GSK-3, the method comprising contacting cells expressing GSK-3 with an inhibitory effective amount of a compound which comprises a negatively charged group and at least one amino moiety-containing group being linked therebetween via a spacer, wherein said spacer has a length, structure and flexibility suitable for enabling at least one interaction between said negatively charged group and a first binding site in the catalytic domain of a G. K-3 and at least one interaction between said amino moiety-containing group and a second binding site in the catalytic domain of a GSK-3.
A method of potentiating insulin signaling, the method comprising contacting insulin responsive cells with an effective amount of a compound which comprises a negatively charged group and at least one amino moiety-containing group being linked therebetween via a spacer, wherein said spacer has a length, structure and flexibility suitable for enabling at least one interaction between said negatively charged group and a first binding site in the catalytic domain of a GSK-3 and at least one interaction between said amino moiety-containing group and a second binding site in the catalytic domain of a GSK-3.
A method of treating a biological condition associated with an activity of GSK-3, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound which comprises a negatively charged group and at least one amino moiety-containing group being linked therebetween via a spacer, wherein said spacer has a length, structure and flexibility suitable for enabling at least one interaction between said negatively charged group and a first binding site in the catalytic domain of a GSK-3 and at least one interaction between said amino moiety-containing group and a second binding site in the catalytic domain of a GSK-3.
Dependencies are inferred from the claim text.