Therapeutic methods for type I diabetes
The invention relates to the treatment and prevention of type I diabetes. More specifically, the invention relates to compounds that treat or prevent the body's immune system from destroying β-cells (i.e., insulin-producing cells in the pancreatic islets of Langerhans) by inhibition of JNK2, selective inhibition of JNK2, or inhibition of the expression of the MAPK9 gene or gene product. In one embodiment, the present invention contemplates the diagnosis, identification, production, and use of compounds which modulate MAPK9 gene expression or the activity of the MAPK9 gene product including but not limited to, JNK2, the nucleic acid encoding MAPK9 and homologues, analogues, and deletions thereof, as well as antisense, ribozyme, triple helix, antibody, and polypeptide molecules as well as small inorganic molecules. The present invention contemplates a variety of pharmaceutical formulations and routes of administration for such compounds.
1. A method for treating type I diabetes in a subject, comprising administering a compound that inhibits the activity of JNK2 in said subject, wherein said compound has the following formula:
wherein:
Ar 1 is a substituted or unsubstituted aryl or heteroaryl group; X is O or S;
Ar 2 a substituted or unsubstituted aryl or heteroaryl group;
R 1 and R 2 are independently selected from the group consisting of hydrogen and a C 1 -C 6 alkyl group;
R a , R a′ , R b , R b′ are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; or R a′ and R a or R b′ together with the carbon atoms they are linked, form a substituted or unsubstituted 5-8-membered saturated, partially unsaturated or aromatic ring containing optionally one or more heteroatoms selected from O, N, S;
R 3 is selected from the group consisting of H, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; aryl C 1 -C 10 -alkyl and heteroaryl C 1 -C 10 -alkyl; or R 3 and R a or R a′ form, together with the N atom linked to R 3 , a 5-8-membered saturated ring, containing optionally at least one further heteroatom selected from O, N, S;
R 4 is selected from the group consisting of H and —C(H)R 5 R 6 ;
R 5 and R 6 are independently selected from the group consisting of H, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, hetero aryl, 3-8 membered cycloalkyl optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; aryl C 1 -C 10 -alkyl and heteroaryl C 1 -C 10 -alkyl;
m is an integer from 1 to 5, n is an integer from 0 to 2, and p is an integer from 1 to 10.
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