Preventing or treating neurodegenerative or dementia diseases characterized by molecular pathology of microtubuli-associated tau protein comprises administering a K252a derivative

摘要

Preventing or treating neurodegenerative or dementia diseases characterized by molecular pathology of microtubuli-associated tau protein comprises administering a K252a derivative (I). Preventing or treating neurodegenerative or dementia diseases characterized by molecular pathology of microtubuli-associated tau protein comprises administering a K252a derivative (I) of formula 1 or its salt. R1COOR or CONHR; R : H, Me, Et or cyclopropyl; R2, R3H, F, Me, OH, NH2, NHMe or NMe2; and Z : (H,H) or O. Independent claims are also included for: (1) identifying inhibitors of neurofibrillar degeneration and their activity by incubating metabolically active mammalian brain section tissue with candidate compounds at various concentrations, provoking tau hyperphosphorylation with a PP2A (not defined) inhibitor, quantifying tau phosphoepitopes in the tissue or tissue extracts by immunoassay, and comparing the phosphoepitope provocation with that of untreated control tissue; (2) determining a suitable dose of an inhibitor of paired helical filament-like tau hyperphosphorylation for treating a disease characterized by neurofibrillar pathology by titrating the inhibitor in brain sections stimulated with a PP2A inhibitor to determine effective tissue concentrations and pharmacokinetically evaluating a dosage scheme to produce effective concentrations in the CNS of a subject; and (3) determining a suitable dose of an inhibitor of paired helical filament-like tau hyperphosphorylation for treating a disease characterized by neurofibrillar pathology by determining a normal level of a paired helical filament-like tau phosphoepitope in the cerebrospinal fluid of healthy control subjects of the same age group, increasing the dose of an inhibitor in a subject suffering from a form of neurofibrillar degeneration at intervals of several weeks or administering increasing doses of an inhibitor identified as above to individual subjects, immunochemically evaluating the reduction in paired helical filament-like tau phosphoepitope in the cerebrospinal fluid of the same subject immediately before the start of treatment and again after several weeks of continuous administration of the inhibitor, and comparing the level of paired helical filament-like tau phosphoepitope in cerebrospinal fluid before and after the start of treatment of a subject suffering from a form of neurofibrillar degeneration, and determining the effective dose as one that reduces the paired helical filament-like tau phosphoepitope level to the range occurring in healthy controls of the same age group. [Image] ACTIVITY : Neuroprotective; Nootropic; Antiparkinsonian; Cerebroprotective. MECHANISM OF ACTION : Tau hyperphosphorylation inhibitor. 9(S),12(R)-Epoxy-2,3,9,10,11,12-hexahydro-10(R)-amino-9-methyl-1-oxo-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxamide had an IC50 of 200 nM for inhibiting phosphorylation of AP422, AT8, AT100 and Thr231 epitopes in rat hippocampus sections, and 400 nM for inhibiting phosphorylation of the Ser262 epitope.