- Covalent docking modelling-based discovery of tripeptidyl epoxyketone proteasome inhibitors composed of aliphatic-heterocycles
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The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event. Compound 1 composed of a six-membered heterocyclic ring was designed by using covalent docking. With a possible different binding mode from the clinical compound Carfilzomib, it occupied the S5 pocket of 20S proteasome and showed favorable inhibitory activity. Subsequently optimization and evaluation were taken place. Among these compounds, 11h demonstrated extraordinary in vitro inhibitory activity and selectivity, and good in vivo proteasome inhibitory activity, a favorable pharmacokinetic profile and xenograft tumor inhibition. The possible binding pattern of compound 11h against proteasome was further fully explored via calculations, providing a theoretical basis for finding potent proteasome inhibitors.
- Dong, Xiao-Wu,Zhang, Jian-Kang,Xu, Lei,Che, Jin-Xin,Cheng, Gang,Hu, Xiao-Bei,Sheng, Li,Gao, An-Hui,Li, Jia,Liu, Tao,Hu, Yong-Zhou,Zhou, Yu-Bo
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supporting information
p. 602 - 614
(2019/01/11)
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- VISUAL FUNCTION DISORDER IMPROVING AGENTS
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The present invention provides a visual function disorder improving agent containing a compound having Rho kinase inhibitory activity, particularly (R)-(+)-N-(1H-pyrrolo?2,3-büpyridin-4-yl)-4-(1-aminoethyl)benzamide, as an effective component. This agent
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- Preventives/remedies for kidney diseases
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A compound having a Rho kinase inhibitory activity, such as (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)-cyclohexane, has a renal interstitial fibrosis inhibitory action in renal interstitial fibrosis model mice and various other actions, and therefore, is useful as an agent for the prophylaxis or treatment of renal diseases.
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- Antitumor effect potentiators
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When used concurrently with an antitumor agent, a compound having a Rho kinase inhibitory activity, such as (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide, reinforces an antitumor effect of the antitumor agent and is useful as an antitumor effect potentiator. Particularly, a compound having a Rho kinase inhibitory activity used with an antitumor agent in combination can reduce the dose of the antitumor agent, which in turn affords provision of a sufficient effect and/or reduction of side effects.
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- Agent for prophylaxis and treatment of glaucoma
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An agent for the prophylaxis and treatment of glaucoma, which contains a compound having a Rho kinase inhibitory activity, particularly an agent for the prophylaxis and treatment of glaucoma, which contains a compound of the formula (I) wherein each symbol is as defined in the specification, as the compound having a Rho kinase inhibitory activity, is provided. The agent for the prophylaxis and treatment of glaucoma of the present invention is a novel agent for the prophylaxis and treatment of glaucoma and has intraocular pressure lowering action, optic disc blood flow improving action and aqueous humor outflow promoting action.
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- PREVENTIVES/REMEDIES FOR ANGIOSTENOSIS
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An agent for the prophylaxis and treatment of vascular constriction is provided, which contains a compound having a Rho kinase inhibitory activity. In particular, a compound having a Rho kinase inhibitory activity, for example, (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, suppresses regenerative intima proliferation after disorder of blood vessel and has various other actions. Therefore, it is useful as an agent for the prophylaxis and treatment of vascular constriction, specifically, an agent for the prophylaxis and treatment of vascular constriction induced by disorder of vascular wall, such as vascular restenosis that occurs after an operation of percutaneus transluminal coronary angioplasty, vascular restenosis that occurs after an operation of percutaneus transluminal angioplasty, vascular constriction that occurs after vascular reconstruction, such as DCA, operation of intravascular indwelling of stent and the like, and vascular constriction that occurs after organ transplantation.
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- PREVENTIVES/REMEDIES FOR LIVER DISEASES
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The invention provides an agent for the prophylaxis and treatment of liver disease and an activation inhibitor of hepatic stellate cells, which contains a compound having a Rho kinase inhibitory activity. The compound having a Rho kinase inhibitory activity, such as (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, is useful for the prophylaxis and treatment of liver diseases, such as hepatitis, hepatic fibrosis, hepatic cirrhosis, hepatic cancer and the like, because it has various actions, such as a superior inhibitory action on the activation of hepatic stellate cell, suppressive action on hepatic fibrogenesis in liver tissues and the like.
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- PREVENTIVES/REMEDIES FOR INTERSTITIAL PNEUMONIA AND PULMONARY FIBROSIS
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An agent for the prophylaxis and treatment of interstitial pneumonia and pulmonary fibrosis, which contains a compound having a Rho kinase inhibitory activity, particularly an agent for the prophylaxis and treatment of interstitial pneumonia and pulmonary fibrosis, which contains a compound of the formula (I) wherein each symbol is as defined in the specification, as the compound having a Rho kinase inhibitory activity, is provided.
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