Takayuki Mimura

Ferric Citrate Hydrate, a New Phosphate Binder, Prevents the Complications of Secondary Hyperparathyroidism and Vascular Calcification

Background/Aims: Ferric citrate hydrate (JTT-751) is being developed as a treatment for hyperphosphatemia in chronic kidney disease patients, and shows serum phosphorus-reducing effects on hyperphosphatemia in hemodialysis patients. We examined whether JTT-751 could reduce phosphorus absorption in normal rats and prevent the progression of ectopic calcification, secondary hyperparathyroidism and bone abnormalities in chronic renal failure (CRF) rats. Methods: Normal rats were fed a diet containing 0.3, 1 or 3% JTT-751 for 7 days. The effects of JTT-751 on phosphorus absorption were evaluated with fecal and urinary phosphorus excretion. Next, a CRF model simulating hyperphosphatemia was induced by feeding rats a 0.75% adenine diet. After 21 days of starting the adenine diet feeding, 1 or 3% JTT-751 was administered for 35 days by dietary admixture. The serum phosphorus levels and mineral parameters were measured. Calcification in the aorta was examined biochemically and histopathologically. Hyperparathyroidism and bone abnormalities were evaluated by histopathological analysis of the parathyroid and femur, respectively. Results: In normal rats, JTT-751 increased fecal phosphorus excretion and reduced phosphorus absorption and urinary phosphorus excretion. In CRF rats, JTT-751 reduced serum phosphorus levels, the calcium-phosphorus product and calcium content in the aorta. Serum intact parathyroid hormone levels and the incidence and severity of parathyroid hyperplasia were also decreased. JTT-751 reduced femoral bone fibrosis, porosity and osteoid formation. Conclusions: JTT-751 could bind with phosphate in the gastrointestinal tract, increase fecal phosphorus excretion and reduce phosphorus absorption. JTT-751 could prevent the progression of ectopic calcification, secondary hyperparathyroidism and bone abnormalities in rats.

Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates as ADAMTS-5 (Aggrecanase-2) inhibitors

A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 with an Agg-2 IC50=7.4 nM, the most potent ADAMTS-5 inhibitor reported so far.

Novel N-substituted 2-phenyl-1-sulfonylamino-cyclopropane carboxylates as selective ADAMTS-5 (Aggrecanase-2) inhibitors

A series of N-substituted sulfonylamino-alkanecarboxylate ADAMTS-5 (Aggrecanase-2) inhibitors has been synthesized and the in vitro enzyme SAR is discussed. This report is the first example of carboxylate-based ADAMTS-5 inhibitors which show strong potency of IC(50)<0.1muM with excellent selectivity over MMP-1 and TACE.

Involvement of the Endogenous Cannabinoid 2 Ligand 2-Arachidonyl Glycerol in Allergic Inflammation

Background: Cannabinoid (CB) 2 is expressed on immune and inflammatory cells. Identification of 2-arachidonyl glycerol (2-AG) and anandamide as endogenous CB2 ligands has allowed investigations of the roles of CB2 and its endogenous ligand system in inflammatory cells. However, the roles of this receptor-ligand system in inflammatory and allergic immune responses in vivo have not been fully elucidated. Methods: Two mouse allergy models, namely ear dermatitis induced by 2,4-dinitrofluorobenzene and allergic bronchitis induced by ovalbumin, were analyzed for 2-AG amounts in allergic tissues, with reference to allergic and inflammatory symptoms. To investigate the gene expression via CB2 in inflammatory cells, human promyelocytic HL-60 cells were stimulated by the CB2 ligand 2-AG ether and analyzed using a DNA microarray. Results: In the ear dermatitis model, the 2-AG amount increased upon serial 2,4-dinitrofluorobenzene challenges and was correlated with ear weight gain. The increased ear thickness in this allergy model was clearly suppressed in CB2 knockout mice, suggesting that the generated endogenous CB2 ligands induce ear thickness through aberrant inflammatory responses and remodeling mediated via CB2. In the allergic bronchitis model, the 2-AG level in bronchoalveolar lavage was increased and sustained during the elevation of inflammatory cell infiltration. The DNA microarray analysis of human HL-60 cells revealed that 2-AG ether induced expressions of not only inflammatory chemokines/cytokines but also of cell growth factors. Conclusion: Our data strongly suggest that endogenous CB2 ligands upregulated upon disease progression in allergic models are involved in aberrant alterations of both inflammatory responses and tissue cell growth.

The cannabinoid receptor-2 is involved in allergic inflammation

AIM To investigate the role of cannabinoid receptor-2 (CB2) in allergic inflammation in CB2 knockout (CB2-KO) mice. MAIN METHODS The swelling reaction of the pinna to various stimuli was compared between CB2-KO and wild-type (WT) mice in terms of edema and acanthosis. KEY FINDINGS Ear swelling induced by repeated application of 2,4-dinitrofluorobenzene in CB2-KO mice was significantly decreased compared with that in WT mice. In an ovalbumin model, pinna edema was significantly suppressed in CB2-KO mice in comparison with that in WT mice. The contribution of CB2 to edema was investigated in a more extreme dermatitis model using oxazolone. Delayed-type hypersensitivity reactions in this model were also suppressed in CB2-KO mice. In each of these three different allergic dermatitis models, there was a significant decrease in edema and acanthosis in CB2-KO mice compared with WT mice. SIGNIFICANCE These results clearly demonstrate that CB2 and its endogenous ligands participate not only in the acute, edematous phase of allergic dermatitis, but also in the chronic irreversible acanthosis reaction.