ABSTRACT
Because no drug exists that halts or even slows any neurodegenerative disease, developing effective therapeutics for any prion disorder is urgent. We recently reported two compounds (IND24 and IND81) with the 2-aminothiazole (2-AMT) chemical scaffold that almost doubled the incubation times in scrapie prion-infected, wild-type (wt) FVB mice when given in a liquid diet. Remarkably, oral prophylactic treatment with IND24 beginning 14 days prior to intracerebral prion inoculation extended survival from â¼120 days to over 450 days. In addition to IND24, we evaluated the pharmacokinetics and efficacy of five additional 2-AMTs; one was not followed further because its brain penetration was poor. Of the remaining four new 2-AMTs, IND114338 doubled and IND125 tripled the incubation times of RML-inoculated wt and Tg4053 mice overexpressing wt mouse prion protein (PrP), respectively. Neuropathological examination of the brains from untreated controls showed a widespread deposition of self-propagating, ß-sheet-rich "scrapie" isoform (PrP(Sc)) prions accompanied by a profound astrocytic gliosis. In contrast, mice treated with 2-AMTs had lower levels of PrP(Sc) and associated astrocytic gliosis, with each compound resulting in a distinct pattern of deposition. Notably, IND125 prevented both PrP(Sc) accumulation and astrocytic gliosis in the cerebrum. Progressive central nervous system dysfunction in the IND125-treated mice was presumably due to the PrP(Sc) that accumulated in their brainstems. Disappointingly, none of the four new 2-AMTs prolonged the lives of mice expressing a chimeric human/mouse PrP transgene inoculated with Creutzfeldt-Jakob disease prions.
Subject(s)
Brain/drug effects , Brain/pathology , PrPSc Proteins/metabolism , Thiazoles/chemistry , Thiazoles/pharmacology , Animals , Brain/metabolism , Dose-Response Relationship, Drug , Female , Humans , Mice , PrPSc Proteins/genetics , Scrapie/pathology , Species Specificity , Survival Analysis , Survival Rate , Thiazoles/pharmacokinetics , Thiazoles/therapeutic use , Transgenes/genetics , Treatment OutcomeABSTRACT
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Subject(s)
I-kappa B Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Quinolines/chemistry , Semicarbazides/chemistry , Thiourea/analogs & derivatives , Animals , Dogs , Female , Hepatocytes/metabolism , High-Throughput Screening Assays , Humans , I-kappa B Kinase/metabolism , Macaca mulatta , Male , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Semicarbazides/chemical synthesis , Semicarbazides/pharmacokinetics , Structure-Activity Relationship , Thiourea/chemical synthesis , Thiourea/chemistry , Thiourea/pharmacokineticsABSTRACT
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
