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Your search keyword '"Tokuhara H"' showing total 2 results
Start Over Author "Tokuhara H" Topic spiro compounds
2 results on '"Tokuhara H"'

1. Design and Synthesis of Novel Spiro Derivatives as Potent and Reversible Monoacylglycerol Lipase (MAGL) Inhibitors: Bioisosteric Transformation from 3-Oxo-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-6-yl Moiety.

Author

Ikeda S, Sugiyama H, Tokuhara H, Murakami M, Nakamura M, Oguro Y, Aida J, Morishita N, Sogabe S, Dougan DR, Gay SC, Qin L, Arimura N, Takahashi Y, Sasaki M, Kamada Y, Aoyama K, Kimoto K, and Kamata M

Subjects
Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Models, Molecular, Molecular Structure, Monoacylglycerol Lipases metabolism, Oxazines chemistry, Spiro Compounds chemical synthesis, Spiro Compounds chemistry, Structure-Activity Relationship, Drug Design, Enzyme Inhibitors pharmacology, Monoacylglycerol Lipases antagonists & inhibitors, Oxazines pharmacology, Spiro Compounds pharmacology
Abstract

The therapeutic potential of monoacylglycerol lipase (MAGL) inhibitors in central nervous system-related diseases has attracted attention worldwide. However, the availability of reversible-type inhibitor is still limited to clarify the pharmacological effect. Herein, we report the discovery of novel spiro chemical series as potent and reversible MAGL inhibitors with a different binding mode to MAGL using Arg57 and His121. Starting from hit compound 1 and its co-crystal structure with MAGL, structure-based drug discovery (SBDD) approach enabled us to generate various spiro scaffolds like 2a (azetidine-lactam), 2b (cyclobutane-lactam), and 2d (cyclobutane-carbamate) as novel bioisosteres of 3-oxo-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-6-yl moiety in 1 with higher lipophilic ligand efficiency (LLE). Optimization of the left hand side afforded 4f as a promising reversible MAGL inhibitor, which showed potent in vitro MAGL inhibitory activity (IC 50 6.2 nM), good oral absorption, blood-brain barrier penetration, and significant pharmacodynamic changes (2-arachidonoylglycerol increase and arachidonic acid decrease) at 0.3-10 mg/kg, po. in mice.

Published
2021
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2. Antimalarial activity of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) and its carboxylic acid derivatives.

Author

Sato A, Kawai S, Hiramoto A, Morita M, Tanigawa N, Nakase Y, Komichi Y, Matsumoto M, Hiraoka O, Hiramoto K, Tokuhara H, Masuyama A, Nojima M, Higaki K, Hayatsu H, Wataya Y, and Kim HS

Subjects
Animals, Antimalarials chemical synthesis, Antimalarials therapeutic use, Carbon chemistry, Carbon metabolism, Carboxylic Acids chemistry, Drug Evaluation, Preclinical, Ferrous Compounds metabolism, Free Radicals chemistry, Free Radicals metabolism, Hexanols chemical synthesis, Hexanols therapeutic use, Humans, Inhibitory Concentration 50, Malaria parasitology, Malaria, Falciparum parasitology, Mice, Mice, Inbred ICR, Oxidation-Reduction, Peroxides chemistry, Peroxides metabolism, Plasmodium berghei growth & development, Plasmodium falciparum growth & development, Spiro Compounds chemical synthesis, Spiro Compounds therapeutic use, Structure-Activity Relationship, Antimalarials administration & dosage, Hexanols administration & dosage, Malaria drug therapy, Malaria, Falciparum drug therapy, Plasmodium berghei drug effects, Plasmodium falciparum drug effects, Spiro Compounds administration & dosage
Abstract

Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cyclic peroxides having carboxyl functionality was prepared based on the antimalarial candidate, N-251, and their antimalarial activities were determined. The reactions of N-89 and its derivatives with Fe(II) demonstrated a highly efficient formation of the corresponding carbon radical which may be suspected as a key for the antiparasitic activity., (Published by Elsevier Ireland Ltd.)

Published
2011
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