In vitro enzyme-mimic activity and in vivo therapeutic potential of HSJ-0017, a novel Mn porphyrin-based antioxidant enzyme mimic.

Manganese (III) 5, 10, 15, 20-tetrakis [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, designated HSJ-0017, is a novel antioxidant enzyme mimic. The aim of the present study was to investigate the enzyme-mimic activity and the therapeutic potential of HSJ-0017 in free radical-related diseases. Superoxide dismutase (SOD) mimic activity was measured by the nitroblue tetrazolium chloride monohydrate reduction assay. Catalase (CAT) mimic activity was measured based on the decomposition of hydrogen peroxide. The antitumor, radioprotective and chemoprotective effects of HSJ-0017 were evaluated in H22 or S180 tumor-bearing Kunming mice. The anti-inflammatory and hepatoprotective effects were, respectively, evaluated in histamine-induced edema model and CCl4-induced hepatic damage model in Wistar rats. HSJ-0017 over a concentration range of 0.001-10 µmol/L significantly inhibited the generation of superoxide anion. Significant hydrogen peroxide scavenging activity was observed when the concentration of HSJ-0017 was higher than 0.01 µmol/L. HSJ-0017 at a dose of 3.0 mg/kg exhibited significant antitumor effect on S180 tumor xenografts, whereas no significant antitumor effect was observed in H22 tumor xenografts. HSJ-0017 at a dose of 3.0 mg/kg enhanced the antitumor effects of radiotherapy and chemotherapy, and reduced their toxicity. However, HSJ-0017 counteracted the antitumor effects of radiotherapy when administered simultaneously with radiotherapy. HSJ-0017 showed significant anti-inflammatory and hepatoprotective effects. Our results demonstrate that HSJ-0017 exhibits antioxidant, antitumor, anti-inflammatory, radioprotective, chemoprotective, and hepatoprotective effects. It is a potent dual SOD/CAT mimic.

Pharmacokinetics, tissue distribution and excretion of manganese (III) meso-tetra [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, a novel superoxide dismutase mimic, in Wistar rats.

Manganese (III) 5, 10, 15, 20-tetrakis [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, designated HSJ-0017, is a novel superoxide dismutase mimic. It exhibits strong free-radical scavenging activities in vitro and in vivo. The aim of the present study was to investigate the pharmacokinetics, tissue distribution and excretion of HSJ-0017 in Wistar rats following a single intravenous administration. Wistar rats were given different doses of HSJ-0017 by single intravenous injection. Biological samples of rats were collected and were assayed by the HPLC method. The pharmacokinetics, tissue distribution and excretion of HSJ-0017 were investigated. The pharmacokinetic data of HSJ-0017 in rats following intravenous injection was best-fit by a two-compartment model. T max of HSJ-0017 in plasma following intravenous injection was 0.083 h. AUC and plasma drug concentration were found to increase in a dose-related fashion. The highest concentrations of HSJ-0017 were detected in the liver (82.25 ± 13.99 µg/g) of rats, followed by the kidney, small intestine, lung, plasma, heart, spleen, and stomach within 2 h postdose. No HSJ-0017 was detected in the uterus, parorchis or brain of rats during the 24-h period of examination. The total cumulative excretion of HSJ-0017 in rat bile and urine were found to be 78.85 and 67.58 %, respectively. Our study has led to the view that the HSJ-0017 can be rapidly distributed to tissues after intravenous administration, but cannot diffuse through the blood-brain barrier. The faecal and biliary excretion of unchanged HSJ-0017 are the major routes of HSJ-0017 elimination.

Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer.

A novel 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione series of MEK inhibitors has been developed using structure-based drug design. Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment.

Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinase inhibitor with anti-tumor activity in preclinical assays.

We describe the identification of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine (3), a potent, orally active Src inhibitor with desirable PK properties, demonstrated activity in human tumor cell lines and in animal models of tumor growth.

Discovery and preliminary structure-activity relationship studies of novel benzotriazine based compounds as Src inhibitors.

We report the discovery and preliminary SAR studies of a series of structurally novel benzotriazine core based small molecules as inhibitors of Src kinase. To the best of our knowledge, benzotriazine template based compounds have not been reported as kinase inhibitors. The 3-(2-(1-pyrrolidinyl)ethoxy)phenyl analogue (43) was identified as one of the most potent inhibitors of Src kinase.

Preparation and characterization of porphyrin nanoparticles.

The synthesis, characterization, and stability of porphyrin nanoparticles of 20-200 nm diameter presented herein is general for meso arylporphyrins. The elegance of the method lies in its simplicity. This work shows that the agent used to prevent agglomeration can be covalently attached to the dye forming the particle or be part of the solvent system. It also demonstrates that these and other types of dyes with a range of photonic properties do not need to be prepared by inclusion in external matrices or by designed self-assembly a priori. The matrix may severely limit the functionality of the particles in the former case, and at present this size of particle is difficult to achieve via the latter.