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Your search keyword '"Morokata T"' showing total 5 results
Start Over Author "Morokata T" Topic receptors, ccr3
5 results on '"Morokata T"'

1. Pyrrolidinyl phenylurea derivatives as novel CCR3 antagonists.

Author

Nitta A, Iura Y, Inoue H, Sato I, Morihira K, Kubota H, Morokata T, Takeuchi M, Ohta M, Tsukamoto S, Imaoka T, and Takahashi T

Subjects
Administration, Oral, Animals, Biological Availability, Half-Life, Macaca fascicularis, Phenylurea Compounds chemical synthesis, Phenylurea Compounds pharmacokinetics, Pyrrolidines chemical synthesis, Pyrrolidines pharmacokinetics, Receptors, CCR3 metabolism, Phenylurea Compounds chemistry, Pyrrolidines chemistry, Receptors, CCR3 antagonists & inhibitors
Abstract

Optimization starting with our lead compound 1 (IC(50)=4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC(50)=1.7 nM), a potent and orally active CCR3 antagonist., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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2. Discovery and structure-activity relationships of urea derivatives as potent and novel CCR3 antagonists.

Author

Nitta A, Iura Y, Tomioka H, Sato I, Morihira K, Kubota H, Morokata T, Takeuchi M, Ohta M, Tsukamoto S, Imaoka T, and Takahashi T

Subjects
Drug Evaluation, Preclinical, Humans, Naphthalenes chemical synthesis, Naphthalenes chemistry, Naphthalenes metabolism, Proline chemistry, Protein Binding, Pyrrolidines chemical synthesis, Pyrrolidines chemistry, Pyrrolidines metabolism, Receptors, CCR3 metabolism, Structure-Activity Relationship, Urea chemical synthesis, Urea metabolism, Receptors, CCR3 antagonists & inhibitors, Urea analogs & derivatives
Abstract

The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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3. Synthesis, biological evaluation, and metabolic stability of acrylamide derivatives as novel CCR3 antagonists.

Author

Sato I, Morihira K, Inami H, Kubota H, Morokata T, Suzuki K, Ohno K, Iura Y, Nitta A, Imaoka T, Takahashi T, Takeuchi M, Ohta M, and Tsukamoto S

Subjects
Acetamides chemistry, Acetamides pharmacology, Acrylamides chemical synthesis, Acrylamides pharmacokinetics, Animals, Anti-Allergic Agents chemistry, Anti-Allergic Agents pharmacokinetics, Haplorhini, Humans, Mice, Microsomes, Liver metabolism, Naphthalenes chemistry, Naphthalenes pharmacology, Piperidines chemical synthesis, Piperidines chemistry, Piperidines pharmacology, Protein Isoforms antagonists & inhibitors, Protein Isoforms metabolism, Receptors, CCR3 metabolism, Thermodynamics, Acetamides chemical synthesis, Acrylamides chemistry, Anti-Allergic Agents chemical synthesis, Naphthalenes chemical synthesis, Receptors, CCR3 antagonists & inhibitors
Abstract

Our laboratory has identified several acrylamide derivatives with potent CCR3 inhibitory activity. In the present study, we evaluated the in vitro metabolic stability (CL(int); mL/min/kg) of these compounds in human liver microsomes (HLMs), and assessed the relationship between their structures and CL(int) values. Among the compounds identified, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-[1-(2-hydroxybenzoyl)piperidin-4-ylidene]acetamide (30j) was found to be a potent inhibitor (IC(50)=8.4nM) with a high metabolic stability against HLMs.

Published
2009
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4. Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition.

Author

Sato I, Morihira K, Inami H, Kubota H, Morokata T, Suzuki K, Iura Y, Nitta A, Imaoka T, Takahashi T, Takeuchi M, Ohta M, and Tsukamoto S

Subjects
Calcium chemistry, Calcium metabolism, Cytoplasm chemistry, Cytoplasm metabolism, Humans, Hydrocarbons, Fluorinated chemical synthesis, Inhibitory Concentration 50, Naphthalenes chemical synthesis, Receptors, CCR3 metabolism, Structure-Activity Relationship, Cytochrome P-450 CYP2D6 Inhibitors, Drug Design, Hydrocarbons, Fluorinated pharmacology, Naphthalenes pharmacology, Receptors, CCR3 antagonists & inhibitors
Abstract

In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using ClogD(7.4) values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC(50)=23 nM) with much reduced CYP2D6 inhibitory activity (IC(50)=29,000 nM) compared with 1.

Published
2008
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5. Synthesis and structure-activity relationships of N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide derivatives as novel CCR3 antagonists.

Author

Sato I, Morihira K, Inami H, Kubota H, Morokata T, Suzuki K, Hamada N, Iura Y, Nitta A, Imaoka T, Takahashi T, Takeuchi M, Ohta M, and Tsukamoto S

Subjects
Benzamides chemical synthesis, Calcium metabolism, Chemokine CCL11, Humans, Inhibitory Concentration 50, Precursor Cells, B-Lymphoid, Small Molecule Libraries, Structure-Activity Relationship, Benzamides pharmacology, Receptors, CCR3 antagonists & inhibitors
Abstract

A novel class of potent CCR3 receptor antagonists were designed and synthesized starting from N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide (1),which was found by subjecting our chemical library to high throughput screening (HTS). The CCR3 inhibitory activity of the synthesized compounds against eotaxin-induced Ca(2+) influx was evaluated using CCR3-expressing preB cells. Systematic chemical modifications of 1 revealed that the 6-fluoro-2-naphthylmethyl moiety was essential for CCR3 inhibitory activity in this new series of CCR3 antagonists. Further structural modifications of the benzamide and piperidine moieties of 1 led to the identification of exo-N-{8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3- yl}biphenyl-2-carboxamide [corrected] (31) as a potent CCR3 antagonist with an IC(50) value of 0.020 microM.

Published
2008
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