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Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure-activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.

Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of benzisoxazole compounds as orally active hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.

Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure-activity relationships (SAR) of a series of 4,6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor 1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model.

Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of indazole compounds as hepcidin production inhibitors. The optimization study of compound 1 led to a potent hepcidin production inhibitor 45, which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.

Introduction: Bleeding risk accompanied with anti-platelet drugs is an ultimate dilemma in the treatment of thrombosis patient. Under high shear condition of blood flow, vWF- and collagen-induced signaling pathways are likely to trigger the platelet adhesion to the injured endothelium, which leads to the activation of platelets and arterial thrombus formation. Thus, the recent studies suggest that the selective inhibitor of these pathways is a new target of anti-platelet drugs with lower bleeding risk. We report here a pharmacological profile of DZ-697b, which selectively inhibits platelet aggregation evoked by ristocetin and collagen in vitro and ex vivo. Materials and methods: Human volunteers blood was processed platelet rich plasma (PRP) or washed platelets. PRP aggregation was induced by ristocetin and collagen. To reveal the selectivity, effect of DZ-697b on U46619 (TXA2 analogue), ADP, thrombin and TRAP induced aggregation in the washed platelets were examined. In guinea pigs and cynomolgus monkeys, effects of DZ-697b given orally were also examined on ex vivo PRP aggregation induced by collagen. To investigate the underlying mechanisms of DZ-697b, changes in phosphorylation of FcR γ chain, a common signaling pathway of both vWF- and collagen-induced platelet aggregation, were studied. Results: DZ-697b potently inhibited both ristocetin- and collagen-induced human PRP aggregation, the IC50 being 0.74 μM and 0.55 μM, respectively. In contrast, DZ-697b even at 50 μM did not show any influences on U46619, ADP, thrombin and TRAP induced platelet aggregation. DZ-697b did not affect ovine COX-1 and COX-2 activities at up to 300 μM. The bioavailability of this compound was more than 80% in monkeys. Oral administration of DZ-697b at 1–3 mg/kg significantly and persistently inhibited collagen induced PRP aggregation in monkeys and guinea pigs. Application of ristocetin, vWF, and collagen significantly increased the intensity of phosphorylation of FcR γ chain in washed platelets, which were inhibited by DZ-697b. Conclusion: DZ-697b is an orally active compound which selectively inhibits ristocetin- and collagen-induced platelet aggregation and seems to be promising as novel anti-platelet drug.

Introduction: DZ-697b, a novel anti-platelet compound, selectively inhibits ristocetin- and collagen-induced platelet aggregation, whose pharmacological profile is different from any current medicines. In order to clarify the benefit and risk balance as an anti-thrombotic agent, effects of DZ-697b and aspirin were compared on thrombus formation and gastric bleeding model in guinea pigs. Materials and Methods: Fasted male Hartly guinea pigs under anesthesia were used. DZ-697b (3 - 200 mg/kg) or aspirin (100–300 mg/kg) was orally administered 60 min prior to evaluation. PIT model: Left carotid artery was exposed. Photochemically induced thrombosis (PIT) was initiated by intravenous injection of rose-bengal (10 mg/kg) and exposure of green light (540 nm) to the carotid artery. The time to occlusion by thrombus formation was measured by pulse Doppler blood flow meter. Gastric bleeding model: The stomach was exposed, and esophagus and pylorus were ligated. A cannula was inserted into stomach and gastric hemorrhagic erosion was induced by intraluminal application of 0.7N HCl in a volume of 5mL. Gastric contents were collected every 10 min and measured hemoglobin (Hb) leakage as indices of bleeding. Results: DZ-697b at 3 mg/kg to 100 mg/kg dose-dependently prolonged the time to occlusion in the PIT model, and significant anti-thrombotic effects were observed from 10 mg/kg. However, gastric bleeding induced by 0.7N HCl in gastric lavage was not affected by DZ-697b up to 100 mg/kg. Statistically significant increase in gastric bleeding was observed when DZ-697b was administered at 200 mg/kg. Aspirin at doses of 100–300 mg/kg tended to lengthen the time to thrombotic occlusion in a dose-dependent manner, but there was no statistically significant difference. In contrast, aspirin dose-dependently increased gastric bleeding in the lavage and significant enhancement was found at doses of 200 and 300 mg/kg. Both DZ-697b and aspirin did not give any influences on the area of hemorrhagic erosion induced by gastric application of 0.7N HCl. Thus, the balance between anti-thrombotic effect and bleeding risk of DZ-697b seemed more favorable than that of aspirin. Conclusion: DZ-697b showed anti-thrombotic effects at doses much lower than those inducing gastric bleeding in comparison with aspirin. These results suggest that inhibitors of vWF and collagen related signaling pathway are promising target in the development of new anti-platelet drugs with lower bleeding risk.