- Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase
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Bacterial 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) hydrolyzes adenine from its substrates to form S-methyl-5-thioribose and S-ribosyl-l-homocysteine. MTANs are involved in quorum sensing, menaquinone synthesis, and 5′-methylthioadenosine recycling to S-adenosylmethionine. Helicobacter pylori uses MTAN in its unusual menaquinone pathway, making H. pylori MTAN a target for antibiotic development. Human 5′-methylthioadenosine phosphorylase (MTAP), a reported anticancer target, catalyzes phosphorolysis of 5′-methylthioadenosine to salvage S-adenosylmethionine. Transition-state analogues designed for HpMTAN and MTAP show significant overlap in specificity. Fifteen unique transition-state analogues are described here and are used to explore inhibitor specificity. Several analogues of HpMTAN bind in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. Structural analysis of HpMTAN shows inhibitors extending through a hydrophobic channel to the protein surface. The more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the phosphate nucleophile from the catalytic site.
- Harijan, Rajesh K.,Hoff, Oskar,Ducati, Rodrigo G.,Firestone, Ross S.,Hirsch, Brett M.,Evans, Gary B.,Schramm, Vern L.,Tyler, Peter C.
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- Medicine composition for treating diabetes and nephropathy and preparation method of composition
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The invention relates to a medicine composition for treating diabetes and nephropathy. The medicine composition comprises a compound or a derivative of the compound which serves as a medicinal composition, a filling agent, a stabilizing agent, a flow agent, a flavoring agent and other additives. The invention further discloses a preparation method of the medicine composition for treating the diabetes and the nephropathy. According to the medicine composition, kidney hypertrophy of diabetes patients is relieved by restraining decrease of MMP-9 in kidney expression and expression of TNF-alpha inkidney, so that the kidney is protected.
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Paragraph 0010
(2018/10/02)
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- Integrin expression inhibitors
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The present invention provides an integrin expression inhibitor, and an agent for treating arterial sclerosis, psoriasis, cancer, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, an anticoagulant, or a cancer metastasis suppressor on the basis of an integrin inhibitory action. Namely, it provides an integrin expression inhibitor comprising, as an active ingredient, a sulfonamide compound represented by the following formula (I), a pharmacologically acceptable salt thereof or a hydrate of them. In the formula, B means a C6-C10 aryl ring or 6- to 10-membered heteroaryl ring which may have a substituent and in which a part of the ring may be saturated; K means a single bond, —CH═CH— or —(CR4bR5b)mb— (wherein R4b and R5b are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group; and mb means an integer of 1 or 2); R1 means hydrogen atom or a C1-C6 alkyl group; Z means a single bond or —CO—NH—; and R means a C6-C10 aryl ring or 6- to 10-membered heteroaryl ring which may have a substituent and in which a part of the ring may be saturated, respectively.
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- Heterobicyclic sulfonamide and sulfonic ester derivatives
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Novel heterobicyclic sulfonamide and sulfonic ester derivatives represented by the following general formula(I), which exhibit an antitumor activity and are lowly toxic, and processes for the preparation thereof. A sulfonamide derivative and a sulfonic ester derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof: STR1 wherein A represents a monocyclic or bicyclic aromatic ring which may be substituted; B represents a six-membered unsaturated hydrocarbon ring or a six-membered unsaturated heterocycle containing one nitrogen atom, each of which may be substituted; C represents a five-membered heterocycle containing one or two nitrogen atoms which may be substituted; W represents a single bond or a group represented by formula --CH=CH--; X represents a group represented by formula --N(R1)-- or oxygen; Y represents carbon or nitrogen; Z represents a group represented by formula --N(R2)-- or nitrogen; and R1 and R2 may be the same or different from each other and each represent hydrogen or lower alkyl.
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