Pyrrole based inhibitors of glycogen synthase kinase 3
New pyrrole based compounds, compositions and methods of inhibiting the activity of glycogen synthase kinase (GSK3) in vitro and of treatment of GSK3 mediated disorders in vivo are provided. The methods, compounds and compositions of the invention may be employed alone, or in combination with other pharmacologically active agents in the treatment of disorders mediated by GSK3 activity, such as diabetes, Alzheimer's disease and other neurodegenerative disorders, obesity, atherosclerotic cardiovascular disease, essential hypertension, polycystic ovary syndrome, syndrome X, ischemia, traumatic brain injury, bipolar disorder, immunodeficiency or cancer.
1. A method for treating a GSK 3 -mediated disorder in a human or animal subject, comprising administering to the human or animal subject an amount of a compound of structure III effective to inhibit GSK 3 activity in the subject:
wherein W is absent or is selected from the group consisting of —O—, —S—, —S(O)—, —SO 2 —, —NH—, —NH—CO—, —NR′CO—, —NHSO 2 —, —NR′SO 2 —, —CO—, —CO 2 —, —CH 2 —, —CF 2 —, CHF, —CONH—, —CONR′—, and —NR′—, where R′ is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo;
R 2 and R 3 are independently selected from the group consisting of hydrogen, hydroxyl, and optionally substituted loweralkyl, cycloloweralkyl, cyclicaminoalkyl, alkylaminoalkyl, loweralkoxy, amino, alkylamino, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, and aryl;
R 5 and R 8 are independently selected from the group consisting of hydrogen, halo, and optionally substituted loweralkyl, cycloalkyl, alkoxy, amino, aminoalkoxy, carbonyloxy, aminocarbonyloxy, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, cycloimido, amidino, cycloamidino, guanidinyl, aryl, biaryl, and arylsulfonamido;
R 6 is selected from the group consisting of hydrogen and optionally substituted aryl;
R 7 is selected from the group consisting of hydrogen, hydroxy, halo, carboxyl, nitro, amino, amido, amidino, imido, cyano, sulfonyl, methanesulfonyl, and substituted or unsubstituted alkyl, alkoxy, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkylaminocarbonyloxy, arylamino-carbonyloxy, formyl, loweralkylcarbonyl, loweralkoxycarbonyl, aminocarbonyl, aminoaryl, alkylsulfonyl, sulfonamido, aminoalkoxy, alkylamino, alkylcarbonylamino, alkylaminocarbonylamino, arylaminocarbonylamino, aralkylcarbonylamino, arylcarbonylamino, cycloamido, cyclothioamido, cycloamidino, cycloalkyl, cycloimido, guanidinyl, aryl, arylsulfonyl and arylsulfonamido;
R 9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, nitro, amino, cyano, halo, thioamido, amidino, oxamidino, alkoxyamidino, imidino, guanidinyl, sulfonamido, carboxyl, formyl, loweralkyl, aminoloweralkyl, loweralkylaminoloweralkyl, haloloweralkyl, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, loweralkylaminoloweralkoxy, loweralkylcarbonyl, loweraralkylcarbonyl, lowerheteroaralkylcarbonyl, alkylthio, aryl and aralkyl; the tautomers thereof; or a pharmaceutically acceptable salt thereof;
wherein said GSK3-mediated disorder is selected from the group consisting of diabetes, obesity and syndrome X.
2. A method of claim 1 , wherein the compound is administered by a mode of administration selected from the group consisting of oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intrathecal, buccal, sublingual, intranasal, and rectal administration.
3. A method of claim 1 , which further comprises administering to the subject one or more additional active agents.
4. A method of claim 3 , wherein the GSK3-mediated disorder is diabetes and the additional active agent is selected from the group consisting of insulin, troglitazone, rosiglitazone, pioglitazone, glipizide and metformin.
5. A method of claim 1 wherein the amount of the compound of structure III administered to the human or animal subject is an amount effective to inhibit tau phosphorylation in the subject.
6. A method of claim 1 wherein R 1 , R 2 , and R 3 are hydrogen and R 4 is selected from the group consisting of hydrogen, methyl, ethyl, aminoethyl and dimethylaminoethyl.
7. A method of claim 1 wherein R 1 , R 2 , R 3 , and R 4 , are hydrogen.
8. A method of claim 1 wherein at least one of R 5 and R 7 is a substituted or unsubstituted moiety of the formula:
wherein R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen, nitro, amino, cyano, halo, thioamido, carboxyl, hydroxy, and optionally substituted loweralkyl, loweralkoxy, loweralkoxyalkyl, haloloweralkyl, haloloweralkoxy, aminoalkyl, alkylamino, aminoalkylalkynyl, alkylaminoalkylalkynyl, alkyithjo, alkylcarbonyl amino, aralkylcarbonylamino, heteroaralkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino aminocarbonyl, loweralkylaminocarbonyl, aminoaralkyl, loweralkylaminoalkyl, aryl, heteroaryl, cycloheteroalkyl, aralkyl, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, arylcarbonyloxyalkyl, alkylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, aralkycarbonyloxyalkyl, and heteroaralkcarbonyloxyalkyl.
9. A method of claim 8 wherein R 11 , R 12 , R 14 and R 15 are hydrogen and R 13 is selected from the group consisting of halo, loweralkyl, hydroxy, loweralkoxy, haloloweralkyl, aminocarbonyl, alkylaminocarbonyl and cyano.
10. A method of claim 8 wherein R 11 , R 13 , and R 15 are hydrogen and R 12 and R 14 are independently selected from the group consisting of halo, loweralkyl, hydroxy, loweralkoxy, haloloweralkyl and cyano.
11. A method of claim 8 wherein R 11 , R 12 , R 14 , and R 15 are hydrogen and R 13 is heteroaryl.
12. A method of claim 8 wherein R 11 , R 12 , R 14 , and R 15 are hydrogen and R 13 is a heterocycloalkyl.
13. A method of claim 8 wherein at least one of R 11 , R 12 , R 13 , R 14 , and R 15 are halo and the remainder of R 11 , R 12 , R 13 , R 14 , and R 15 are hydrogen.
14. A method of claim 1 wherein at least one of R 5 and R 8 is selected from the group consisting of dichlorophenyl, difluorophenyl, trifluoromethylphenyl, chlorofluorophenyl, bromochlorophenyl, ethylphenyl, methylchlorophenyl, cyanophenyl, and cyanochlorophenyl.
15. A method of claim 1 wherein R 6 is substituted or unsubstituted aryl.
16. A method in claim 1 wherein R 5 and R 8 are independently hydrogen or lower alkyl.
17. A method in claim 1 wherein the compound of structure III is administered together with a pharmaceutically acceptable carrier.
18. The method of claim 1 wherein the compound of structure III is 1-{3-[(6-amino-5-nitropyridin-2-yl)amino]propyl}-4-(2,4-dichlorophenyl)-N-[(1S)-2-hydroxy-1-methylethyl]-1H-pyrrole-3-carboxamide.