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Your search keyword '"Mikkaichi T"' showing total 2 results
Start Over Author "Mikkaichi T" Journal bioorganic medicinal chemistry letters
2 results on '"Mikkaichi T"'

1. Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors.

Author

Goto T, Shiina A, Murata T, Tomii M, Yamazaki T, Yoshida K, Yoshino T, Suzuki O, Sogawa Y, Mizukami K, Takagi N, Yoshitomi T, Etori M, Tsuchida H, Mikkaichi T, Nakao N, Takahashi M, Takahashi H, and Sasaki S

Subjects
Binding Sites, Cyclic S-Oxides isolation & purification, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Inhibitory Concentration 50, Models, Molecular, Molecular Structure, Phenylacetates isolation & purification, Phosphodiesterase 4 Inhibitors isolation & purification, Cyclic S-Oxides chemistry, Cyclic S-Oxides pharmacology, Phenylacetates chemistry, Phenylacetates pharmacology, Phosphodiesterase 4 Inhibitors chemistry, Phosphodiesterase 4 Inhibitors pharmacology
Abstract

A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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2. Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.

Author

Goto T, Shiina A, Yoshino T, Mizukami K, Hirahara K, Suzuki O, Sogawa Y, Takahashi T, Mikkaichi T, Nakao N, Takahashi M, Hasegawa M, and Sasaki S

Subjects
Animals, Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents therapeutic use, Benzeneacetamides metabolism, Benzeneacetamides therapeutic use, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Cyclic S-Oxides metabolism, Cyclic S-Oxides therapeutic use, Humans, Lipopolysaccharides toxicity, Lung Diseases drug therapy, Lung Diseases pathology, Mice, Phosphodiesterase 4 Inhibitors metabolism, Phosphodiesterase 4 Inhibitors therapeutic use, Protein Binding, Pyrimidines metabolism, Pyrimidines therapeutic use, Spleen cytology, Spleen metabolism, Structure-Activity Relationship, Tumor Necrosis Factor-alpha metabolism, Anti-Inflammatory Agents chemistry, Benzeneacetamides chemistry, Cyclic Nucleotide Phosphodiesterases, Type 4 chemistry, Cyclic S-Oxides chemistry, Phosphodiesterase 4 Inhibitors chemistry, Pyrimidines chemistry
Abstract

2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5 nM) and TNF-α production in mouse splenocytes (IC50=9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
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