Kyoko Minoura

Prevention of progressive joint destruction in collagen‐induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR255031

1 FR255031 (2‐[(7S)‐7‐[5‐(4‐ethylphenyl)‐2‐thienyl]‐1,1‐dioxido‐4‐(2‐pyridinylcarbonyl)hexahydro‐1,4‐thiazepin‐7‐yl]‐N‐hydroxyacetamide) is a novel synthetic matrix metalloproteinase (MMP) inhibitor that inhibits human collagenases (MMP‐1, MMP‐8 and MMP‐13), gelatinases (MMP‐2 and MMP‐9) and membrane type 1 MMP (MT1‐MMP/MMP‐14). FR255031 also inhibits rat collagenase and gelatinase. We studied the effect of FR255031 and Trocade, an inhibitor of collagenase and MMP‐14, on a rat collagen‐induced arthritis (CIA) model. 2 Rat CIA was induced by intradermal injection of type II collagen (IIC) and oral administration of FR255031 or Trocade was performed for 28 days. Body weight loss, hind paw swelling, elevation of serum anti‐IIC antibody, and histological and radiographic scores were evaluated. 3 FR255031 markedly inhibited cartilage degradation in a dose‐dependent manner in the CIA model, but Trocade failed to prevent the degradation. 4 FR255031 at a dose of 100 mg kg−1 also had statistically significant effects on bone destruction and pannus formation and on the recovery of body weight loss on day 28. 5 These results indicate that FR255031 is effective for rat CIA, especially on joint cartilage destruction. These data suggest that as well as collagenases or MT‐MMP, gelatinases are also involved in joint destruction in arthritis.

Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2

Background and purpose:  The lipid phosphatase known as SH2 domain‐containing inositol 5′‐phosphatase 2 (SHIP2) plays an important role in the regulation of the intracellular insulin signalling pathway. Recent studies have suggested that inhibition of SHIP2 could produce significant benefits in treatment of type 2 diabetes. However, there were no small molecule SHIP2 inhibitors and we, therefore, aimed to identify this type of compound.

Effect of zenarestat, an aldose reductase inhibitor, on endoneurial blood flow in experimental diabetic neuropathy of rat

The effects of zenarestat, an aldose reductase inhibitor, on endoneurial blood flow (NBF) were explored in streptozotocin-induced diabetic rats. Rats were maintained on a diet of containing 0.09% zenarestat for 8 weeks, then NBF in the sciatic nerve was measured using microelectrode hydrogen polarography. NBF in the diabetic control rats was significantly lower than values in age-matched control rats, however, NBF was not significantly altered in diabetic rats treated with zenarestat. Direct application of nitric oxide synthase inhibitor, NG-nitro-L-arginine, did not affect NBF in diabetic control rats, whereas this application significantly reduced NBF both in age-matched control and zenarestat treated diabetic rats. Considerable levels of zenarestat were confirmed in the sciatic nerve in the drug treated rats. These data suggest that aldose reductase, such as zenarestat, might restore or prevent the alteration of endoneurial blood flow resulting from an impairment of nitric oxide function.

Thirteen-month inhibition of aldose reductase by zenarestat prevents morphological abnormalities in the dorsal root ganglia of streptozotocin-induced diabetic rats

The dorsal root ganglia (DRG) have been identified as the target tissue in diabetic somatosensory neuropathy. It has been reported that, in the chronically diabetic state, DRG sensory neurons may undergo morphological changes. In this study, we examined the effect of zenarestat, an aldose reductase inhibitor, on the morphological derangement of the DRG and the sural nerve of streptozotocin-induced diabetic rats (STZ rats) over a 13-month period. The cell area of the DRG in STZ rats was smaller than that in normal rats. A decrease in fiber size was apparent in the sural nerve of the STZ rats, and the fiber density was greater. These morphological changes were reversed in zenarestat-treated STZ rats. The data suggest that, in peripheral sensory diabetic neuropathy, hyperactivation of the polyol pathway induces abnormalities not only in peripheral nerve fiber, but also in the DRG, which is an aggregate of primary sensory afferent cell bodies.

Generation and characterization of a potent fully human monoclonal antibody against the interleukin-23 receptor

ABSTRACT Interleukin (IL)‐12 and IL‐23 share a common subunit (p40) and function in T‐helper (Th) 1 and Th17 immunity, respectively. Anti‐IL‐12/23p40 and specific anti‐IL‐23 antibodies are currently in clinical use for psoriasis and undergoing trials for autoimmune diseases. Since expression levels of the IL‐23 receptor are likely to be much lower than those of IL‐23, an anti‐IL‐23 receptor antibody might offer greater promise in inhibiting the IL‐23‐IL‐17 pathways involved in inflammatory disorders. To our knowledge, no anti‐IL‐23 receptor antibody has been trialed in clinical studies to date. This study describes the generation and characterization of AS2762900–00, a fully human monoclonal antibody against the IL‐23 receptor. AS2762900–00 bound both human and cynomolgus monkey IL‐23 receptors. AS2762900–00 showed potent inhibitory effects on IL‐23‐induced Kit‐225 cell proliferation compared to the existing anti‐IL‐12/23p40 antibody, ustekinumab. In a single dose administration pharmacodynamics study in cynomolgus monkeys, 1mg/kg of AS2762900–00 significantly inhibited (> 85%) IL‐23‐induced STAT3 phosphorylation in blood for up to 84 days. Therefore, AS2762900–00 represents a potent novel IL‐23‐IL‐17 pathway inhibitor with the potential to be developed into a new therapy for the treatment of autoimmune diseases.