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Your search keyword '"Rena Nishizawa"' showing total 4 results
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4 results on '"Rena Nishizawa"'

1. Discovery of 4-[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenoxy]benzoic acid hydrochloride: a highly potent orally available CCR5 selective antagonist

Author

Toshihiko Nishiyama, Yoshikazu Takaoka, Hisao Nakai, Katsuya Hisaichi, Kenji Sagawa, Kenji Maeda, Chiaki Minamoto, Shiro Shibayama, Masayuki Murota, Daikichi Fukushima, Hideaki Tada, Hiroaki Mitsuya, and Rena Nishizawa

Subjects
Receptors, CCR5, Stereochemistry, Hydrochloride, Anti-HIV Agents, Clinical Biochemistry, Guinea Pigs, Drug Evaluation, Preclinical, Pharmaceutical Science, Administration, Oral, Diketopiperazines, Biochemistry, Chemical synthesis, Benzoates, Article, chemistry.chemical_compound, Structure-Activity Relationship, Dogs, Oral administration, Drug Discovery, Structure–activity relationship, Animals, Humans, Molecular Biology, Benzoic acid, ADME, Organic Chemistry, Antagonist, Haplorhini, Rats, chemistry, CCR5 Receptor Antagonists, Lactam, Molecular Medicine, Rabbits
Abstract

Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.

Published
2011

2. Spirodiketopiperazine-based CCR5 antagonist: Discovery of an antiretroviral drug candidate

Author

Katsuya Hisaichi, Naoki Matsunaga, Toshihiko Nishiyama, Stephen Jenkinson, Kenji Sagawa, Hisao Nakai, Shiro Shibayama, Hideaki Tada, Yoshikazu Takaoka, Daikichi Fukushima, Rena Nishizawa, Hiroaki Mitsuya, Wieslaw M. Kazmierski, Chiaki Minamoto, and Kenji Maeda

Subjects
Receptors, CCR5, Stereochemistry, Anti-HIV Agents, Clinical Biochemistry, Drug Evaluation, Preclinical, HIV Core Protein p24, Pharmaceutical Science, Administration, Oral, CCR5 receptor antagonist, Diketopiperazines, Biochemistry, Article, chemistry.chemical_compound, Pharmacokinetics, In vivo, Oral administration, Cell Line, Tumor, Drug Discovery, Potency, Animals, Humans, Spiro Compounds, Molecular Biology, Organic Chemistry, Antagonist, Stereoisomerism, In vitro, Rats, chemistry, CCR5 Receptor Antagonists, HIV-1, Microsomes, Liver, Molecular Medicine, Derivative (chemistry)
Abstract

Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.

Published
2010

3. Discovery of orally available spirodiketopiperazine-based CCR5 antagonists

Author

Katsuya Hisaichi, Hisao Nakai, Keisuke Hirai, Kenji Sagawa, Daikichi Fukushima, Toshihiko Nishiyama, Shiro Shibayama, Kenji Maeda, Rena Nishizawa, Hideaki Tada, Masaaki Toda, Hiroaki Mitsuya, Yoshikazu Takaoka, and Hiromu Habashita

Subjects
Receptors, CCR5, Stereochemistry, Anti-HIV Agents, Carboxylic acid, Clinical Biochemistry, Pharmaceutical Science, Administration, Oral, Biological Availability, HIV Infections, Pharmacology, Biochemistry, Chemical synthesis, Article, Piperazines, chemistry.chemical_compound, Pharmacokinetics, Oral administration, In vivo, Drug Discovery, Animals, Humans, Molecular Biology, chemistry.chemical_classification, Dipeptide, Chemistry, Organic Chemistry, Antagonist, Cyclic peptide, Rats, CCR5 Receptor Antagonists, HIV-1, Molecular Medicine, Caco-2 Cells
Abstract

Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented.

Published
2010

4. Spirodiketopiperazine-based CCR5 antagonists: Improvement of their pharmacokinetic profiles

Author

Toshihiko Nishiyama, Masaaki Toda, Yoshikazu Takaoka, Kenji Maeda, Hisao Nakai, Keisuke Hirai, Hiroaki Mitsuya, Daikichi Fukushima, Hiromu Habashita, Rena Nishizawa, Katsuya Hisaichi, Kenji Sagawa, Hideaki Tada, and Shiro Shibayama

Subjects
Anti hiv 1, Receptors, CCR5, Anti-HIV Agents, viruses, Clinical Biochemistry, Human immunodeficiency virus (HIV), HIV Core Protein p24, Pharmaceutical Science, Pharmacology, medicine.disease_cause, Biochemistry, Piperazines, Article, Pharmacokinetics, Oral administration, In vivo, Drug Discovery, medicine, Animals, Humans, Molecular Biology, Chemistry, Anti hiv, Organic Chemistry, Antagonist, virus diseases, Biological activity, Rats, CCR5 Receptor Antagonists, Microsomes, Liver, Molecular Medicine
Abstract

Spirodiketopiperazine-based CCR5 antagonists, showing improved pharmacokinetic profiles without reduction in antagonist activity, were designed and synthesized. We also demonstrate the anti-HIV activity of a representative compound 12, as measured in a p24 assay.

Published
2009

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