Bi-dentate compounds as kinase inhibitors
View Patent ↗The present disclosure provides compound having the general structure A or pharmaceutically acceptable salts thereof: Het-L-P (A) wherein Het is an aromatic moiety comprising a heterocyclic structure mimicking ATP, P is a docking site derived peptide or a docking site peptide mimetic, and L is a linking moiety, wherein L links the ATP mimetic to the docking site peptide moiety. The compounds having the general structure A can serve as inhibitors of kinases, such as the kinases JNK, Erk and p38.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, straight-chained alkyl, branched alkyl, halogen, nitro, or NHC(O)CH 2 C 4 H 3 S;
L is a linking moiety selected from the group consisting of: (a) —CONH—(CH 2 ) n —NH—, (b) —CONH—(CH 2 ) n —NHCO—, (c) —CONH—(CH 2 ) n —CONH—, (d) —(CH 2 ) n —, (e) —O—(CH 2 ) n —O—, (f) —(CH 2 )-phenylene-, and (h) —NHSO 2 —(CH 2 ) n CONH—, wherein n is an integer between 2 and 8; and
P is a peptide consisting of the sequence selected from the group consisting of RPTTLNL (SEQ ID NO:4), N-myristoilated RPTTLNL (SEQ ID NO:4), and GGLNLTTPRGGRRRQRRKKRG (SEQ ID NO:6).
2. The compound of formula I of claim 1 , wherein the compound binds to a JNK kinase docking site.
3. The compound of formula I of claim 1 , wherein L is —CONH—(CH 2 ) n —NH—; and P is a peptide consisting of the sequence selected from RPTTLNL (SEQ ID NO:4), and GGLNLTTPRGGRRRQRRKKRG (SEQ ID NO:6).
4. The compound of formula I of claim 3 , wherein R 1 is hydrogen or straight chain alkyl; and L is —CONH—(CH 2 ) 3 —NH—.
5. The compound of formula I of claim 4 , wherein the compound of formula I has formula II:
or has formula III:
6. A pharmaceutical composition comprising the compound of formula I of claim 1 or the compound of formula II or formula III of claim 5 , and a pharmaceutically acceptable carrier.
7. The composition of claim 6 , further comprising an additional compound selected from the group consisting of: (1) an estrogen receptor modulator, (2) an androgen receptor modulator, (3) retinoid receptor modulator, (4) a cytotoxic agent, (5) an antiproliferative agent, (6) a prenyl-protein transferase inhibitor, (7) an HMG-CoA reductase inhibitor, (8) an HIV protease inhibitor, (9) a reverse transcriptase inhibitor, (10) another angiogenesis inhibitor, and (11) a PPAR-gamma agonist.
8. A method of treating retinal vascularization, comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition of claim 6 .
9. A method of treating diabetic retinopathy, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition of claim 6 .
10. A kit comprising a packaging material and the pharmaceutical composition of claim 6 contained within the packaging material, wherein the packaging material comprises a label which indicates that the composition can be used for treating a disorder, disease, or pathology in a subject in need thereof.