- Discovery of a Plasmodium falciparum Glucose-6-phosphate Dehydrogenase 6-phosphogluconolactonase Inhibitor (R,Z)-N-((1-Ethylpyrrolidin-2-yl)methyl)-2- (2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (ML276) that reduces parasite growth in vitro
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A high-throughput screen of the NIH's MLSMR collection of ~340000 compounds was undertaken to identify compounds that inhibit Plasmodium falciparum glucose-6-phosphate dehydrogenase (Pf G6PD). PfG6PD is important for proliferating and propagating P. falciparum and differs structurally and mechanistically from the human orthologue. The reaction catalyzed by glucose-6-phosphate dehydrogenase (G6PD) is the first, rate-limiting step in the pentose phosphate pathway (PPP), a key metabolic pathway sustaining anabolic needs in reductive equivalents and synthetic materials in fast-growing cells. In P. falciparum, the bifunctional enzyme glucose-6-phosphate dehydrogenase-6- phosphogluconolactonase (Pf GluPho) catalyzes the first two steps of the PPP. Because P. falciparum and infected host red blood cells rely on accelerated glucose flux, they depend on the G6PD activity of PfGluPho. The lead compound identified from this effort, (R,Z)-N-((1-ethylpyrrolidin-2-yl)methyl)-2-(2- fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbox-amide, 11 (ML276), is a submicromolar inhibitor of PfG6PD (IC50 = 889 nM). It is completely selective for the enzyme's human isoform, displays micromolar potency (IC50 = 2.6 μM) against P. falciparum in culture, and has good drug-like properties, including high solubility and moderate microsomal stability. Studies testing the potential advantage of inhibiting Pf G6PD in vivo are in progress.
- Preuss, Janina,Malone, Patrick,Peddibhotla, Satyamaheshwar,Hedrick, Michael P.,Hershberger, Paul,Gosalia, Palak,Milewski, Monika,Li, Yujie Linda,Sugarman, Eliot,Hood, Becky,Suyama, Eigo,Nguyen, Kevin,Vasile, Stefan,Sergienko, Eduard,Mangravita-Novo, Arianna,Vicchiarelli, Michael,McAnally, Danielle,Smith, Layton H,Roth, Gregory P.,Diwan, Jena,Chung, Thomas D.Y.,Jortzik, Esther,Rahlfs, Stefan,Becker, Katja,Pinkerton, Anthony B.,Bode, Lars
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p. 7262 - 7272
(2012/11/07)
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- AMINE COMPOUNDS
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The present invention provide a compound of the formula:wherein ring A represents an aromatic ring optionally having substituents; B, Y and Ya are the same or different and each represents a bond, etc.; R1 and R2 are the same or different and each represents a hydrogen atom, etc.; R3 represents a hydrogen atom, etc.; R4 and R5 are the same or different and each represents a hydrogen, etc.; R6 represents an indolyl group optionally having substituents; and Z and Za are the same or different and each represents a hydrogen atom, etc.; or a salt thereof or a prodrug thereof, having a somatostatin receptor binding inhibition activity and is useful for preventing and/or treating diseases associated with somatostatin.
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Page 212-213
(2010/02/07)
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- HYDROXAMIC ACID DERIVATIVE AND MMP INHIBITOR CONTAINING THE SAME AS ACTIVE INGREDIENT
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A hydroxamic acid derivative represented by the following general formula (1) having selective MMP inhibitory activity, , wherein R1 andR2 each represents hydrogen atom, lower alkyl group, lower haloalkyl etc., X represents methylene
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- Hydroxamic acid derivatives
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A hydroxamic acid derivative represented by formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, which has a matrix metalo-proteinase inhibitor.
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Page column 89-91
(2010/02/06)
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- Quantitative structure-activity relationship study of N-(3-oxo-3,4- dihydro-2H-benzol[1,4]thiazine-6-carbonyl)guanidines as potent na/h exchange inhibitors
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We have previously reported that N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4- dihydro-2H-benzo[1,4]oxazine-6carbonyl)guanidine (4b) methanesulfonate salt (KB-R9032) is a potent and highly water-soluble Na/H exchange inhibitor. In a series of studies on Na/H exc
- Yamamoto, Takeshi,Hori, Manabu,Watanabe, Ikuo,Harada, Kengo,Ikeda, Shoji,Ohtaka, Hiroshi
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p. 843 - 849
(2007/10/03)
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