8 results on '"Takahisa Motomura"'
Search Results
2. Structure-based drug design of novel and highly potent pyruvate dehydrogenase kinase inhibitors
- Author
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Yasuo Terasako, Takahisa Motomura, Genki Mori, Satoki Doi, Yoshitomi Nakane, Takuya Orita, Tomoko Iwanaga, Tatsuo Akaki, Shingo Obika, Ayumi Fujishima, Hiroshi Ueno, Yuki Bessho, Tsuyoshi Adachi, Maki Yamakawa, Yoshinori Hara, Katsutaka Yasue, and Minoru Ubukata
- Subjects
Pyruvate dehydrogenase kinase ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Pyrrolidine ,chemistry.chemical_compound ,Structure-Activity Relationship ,Adenosine Triphosphate ,Amide ,Drug Discovery ,Moiety ,Humans ,Molecular Biology ,Protein Kinase Inhibitors ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,Pyruvate dehydrogenase complex ,Amides ,Enzyme ,chemistry ,Docking (molecular) ,Drug Design ,Molecular Medicine ,Tricyclic - Abstract
Pyruvate dehydrogenase kinases (PDHKs) are fascinating drug targets for numerous diseases, including diabetes and cancers. In this report, we describe the result of our structure-based drug design from tricyclic lead compounds that led to the discovery of highly potent PDHK2 and PDHK4 dual inhibitors in enzymatic assay. The C3-position of the tricyclic core was explored, and the PDHK2 X-ray structure with a representative compound revealed a novel ATP lid conformation in which the phenyl ring of Phe326 mediated the interaction of the Arg258 sidechain and the compound. Compounds with amide linkers were designed to release the ATP lid by forming an intramolecular pi-pi interaction, and these compounds showed single-digit nM IC50 values in an enzymatic assay. We also explored the C4-position of the tricyclic core to reproduce the interaction observed with the C3-position substitution, and the pyrrolidine compound showed the same level of IC50 values. By optimizing an interaction with the Asn255 sidechain through a docking simulation, compounds with 2-carboxy pyrrole moiety also showed single-digit nM IC50 values without having a cation-pi interaction with the Arg258 sidechain.
- Published
- 2021
3. Prediction of Total Drug Clearance in Humans Using Animal Data: Proposal of a Multimodal Learning Method Based on Deep Learning
- Author
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Koichi Handa, Takahisa Motomura, Takeshi Fujiwara, Tatsuru Matsuo, Hiroaki Iwata, Maeda Kazuya, Hideaki Mamada, and Mayumi Matsushita
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Process (engineering) ,Computer science ,Metabolic Clearance Rate ,Pharmaceutical Science ,Inference ,02 engineering and technology ,Drug Elimination Routes ,Machine learning ,computer.software_genre ,030226 pharmacology & pharmacy ,Models, Biological ,03 medical and health sciences ,Animal data ,0302 clinical medicine ,Deep Learning ,Pharmacokinetics ,Total drug clearance ,Species Specificity ,Drug Discovery ,Animals ,Humans ,business.industry ,Drug discovery ,Deep learning ,021001 nanoscience & nanotechnology ,Rats ,Multimodal learning ,Pharmaceutical Preparations ,Artificial intelligence ,0210 nano-technology ,business ,computer - Abstract
Research into pharmacokinetics plays an important role in the development process of new drugs. Accurately predicting human pharmacokinetic parameters from preclinical data can increase the success rate of clinical trials. Since clearance (CL) which indicates the capacity of the entire body to process a drug is one of the most important parameters, many methods have been developed. However, there are still rooms to be improved for practical use in drug discovery research; "improving CL prediction accuracy" and "understanding the chemical structure of compounds in terms of pharmacokinetics". To improve those, this research proposes a multimodal learning method based on deep learning that takes not only the chemical structure of a drug but also rat CL as inputs. Good results were obtained compared with the conventional animal scale-up method; the geometric mean fold error was 2.68 and the proportion of compounds with prediction errors of 2-fold or less was 48.5%. Furthermore, it was found to be possible to infer the partial structure useful for CL prediction by a structure contributing factor inference method. The validity of these results of structural interpretation of metabolic stability was confirmed by chemists.
- Published
- 2020
4. Quinolone Carboxylic Acids as a Novel Monoketo Acid Class of Human Immunodeficiency Virus Type 1 Integrase Inhibitors
- Author
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Yuji Matsuzaki, Hisashi Shinkai, Satoru Ikeda, Hiroshi Kawakami, Motohide Sato, Takashi Matsuda, Takahisa Motomura, Yoshiharu Ito, Masaki Yamashita, Kazunobu Yamataka, and Hisateru Aramaki
- Subjects
medicine.drug_class ,Stereochemistry ,Carboxylic acid ,Carboxylic Acids ,Integrase inhibitor ,HIV Integrase ,Quinolones ,Catalysis ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,HIV Integrase Inhibitors ,chemistry.chemical_classification ,biology ,Elvitegravir ,Quinolone ,Integrase ,Enzyme ,chemistry ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,medicine.drug - Abstract
Human immunodeficiency virus type 1 (HIV-1) integrase is a crucial target for antiretroviral drugs, and several keto-enol acid class (often referred to as diketo acid class) inhibitors have clinically exhibited marked antiretroviral activity. Here, we show the synthesis and the detailed structure-activity relationship of the quinolone carboxylic acids as a novel monoketo acid class of integrase inhibitors. 6-(3-Chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 51, which showed an IC50 of 5.8 nM in the strand transfer assay and an ED50 of 0.6 nM in the antiviral assay, and 6-(3-chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 49, which had an IC50 of 7.2 nM and an ED50 of 0.9 nM, were the most potent compounds in this class. The monoketo acid 49 was much more potent at inhibiting integrase-catalyzed strand transfer processes than 3'-processing reactions, as is the case with the keto-enol acids. Elvitegravir 49 was chosen as a candidate for further studies and is currently in phase 3 clinical trials.
- Published
- 2009
5. Synthesis and Structural Analysis of Oligo(naphthalene-2,3-diyl)s
- Author
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H. Nakamura, Takahisa Motomura, Yoshihiko Ito, Masahiro Murakami, and Michinori Suginome
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Diffraction ,chemistry.chemical_compound ,Series (mathematics) ,Chemistry ,Stereochemistry ,Feature (computer vision) ,General Chemistry ,Protein secondary structure ,Naphthalene - Abstract
Oligo(naphthalene-2,3-diyl)s are synthesized by the palladium-catalyzed cross-coupling reactions of 2-naphthyl-zinc compounds with 2-bromonaphthalene derivatives. An NMR analysis together with an X-ray diffraction study supports the conjecture that the helical secondary structure is a common feature of the assemblies in which naphthalene-like aromatic units are linked together between the β-positions in series.
- Published
- 2005
6. 4-(trans-4-Methylcyclohexyl)-4-Oxobutyric Acid (JTT-608). A New Class of Antidiabetic Agent
- Author
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Itsuo Uchida, Takahisa Motomura, Noboru Furukawa, Takeshi Ohta, Hidekazu Ozeki, and Hisashi Shinkai
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Blood Glucose ,Male ,medicine.medical_specialty ,Carboxylic acid ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,In Vitro Techniques ,Diabetes Mellitus, Experimental ,Structure-Activity Relationship ,Cyclohexanes ,Oral administration ,In vivo ,Internal medicine ,Insulin Secretion ,Drug Discovery ,medicine ,Animals ,Hypoglycemic Agents ,Insulin ,Rats, Wistar ,Pancreas ,chemistry.chemical_classification ,Glucose tolerance test ,medicine.diagnostic_test ,Chemistry ,Fasting ,Glucose Tolerance Test ,Streptozotocin ,In vitro ,Rats ,Butyrates ,Endocrinology ,Animals, Newborn ,Glucose Clamp Technique ,Molecular Medicine ,Stereoselectivity ,medicine.drug - Abstract
During an investigation of drugs for improving the beta-cell response to glucose, we found that 4-cyclohexyl-4-oxobutyric acid selectively improved glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. A series of 4-cycloalkyl-4-oxobutyric acids and related compounds were synthesized and evaluated for their effects on the glucose tolerance test and fasting euglycemia. This study elucidated the structural requirements for drug activity and determined that the optimum compound was 4-(trans-4-methylcyclohexyl)-4-oxobutyric acid 7 (JTT-608). This compound improved glucose tolerance from an oral dose of 3 mg/kg and did not change fasting euglycemia even at an oral dose of 30 mg/kg. Selective improvement of glucose-induced insulin secretion was observed in studies using neonatal streptozotocin rats (nSTZ rats) and perfused pancreases isolated from nSTZ rats.
- Published
- 1998
7. Novel HIV-1 Integrase Inhibitors Derived from Quinolone Antibiotics
- Author
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Hisashi Takatsuki Shinkai, Takashi Matsuda, Motohide Sato, Hiroshi Kawakami, Yoshiharu Ito, Yuji Matsuzaki, Satoru Ikeda, Masao Matsuoka, Eiichi Kodama, Takahisa Motomura, Masaki Yamashita, Kazunobu Yamataka, Hisateru Aramaki, and Wataru Watanabe
- Subjects
medicine.drug_class ,Antibiotics ,Integrase inhibitor ,HIV Integrase ,Quinolones ,Virus ,Cell Line ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Humans ,HIV Integrase Inhibitors ,biology ,Chemistry ,Quinolone ,biology.organism_classification ,Nucleotidyltransferase ,Virology ,Anti-Bacterial Agents ,Integrase ,Enzyme inhibitor ,DNA, Viral ,Lentivirus ,HIV-1 ,biology.protein ,Molecular Medicine - Abstract
The viral enzyme integrase is essential for the replication of human immunodeficiency virus type 1 (HIV-1) and represents a remaining target for antiretroviral drugs. Here, we describe the modification of a quinolone antibiotic to produce the novel integrase inhibitor JTK-303 (GS 9137) that blocks strand transfer by the viral enzyme. It shares the core structure of quinolone antibiotics, exhibits an IC50 of 7.2 nM in the strand transfer assay, and shows an EC50 of 0.9 nM in an acute HIV-1 infection assay.
- Published
- 2006
8. ChemInform Abstract: 4-(trans-4-Methylcyclohexyl)-4-oxobutyric Acid (JTT-608). A New Class of Antidiabetic Agent
- Author
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Takeshi Ohta, Hidekazu Ozeki, Hisashi Shinkai, Noboru Furukawa, Takahisa Motomura, and Itsuo Uchida
- Subjects
Oral dose ,Glucose tolerance test ,Drug activity ,medicine.diagnostic_test ,Chemistry ,Insulin ,medicine.medical_treatment ,medicine ,General Medicine ,Pharmacology ,Streptozotocin ,Insulin secretion ,medicine.drug - Abstract
During an investigation of drugs for improving the β-cell response to glucose, we found that 4-cyclohexyl-4-oxobutyric acid selectively improved glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. A series of 4-cycloalkyl-4-oxobutyric acids and related compounds were synthesized and evaluated for their effects on the glucose tolerance test and fasting euglycemia. This study elucidated the structural requirements for drug activity and determined that the optimum compound was 4-(trans-4-methylcyclohexyl)-4-oxobutyric acid 7 (JTT-608). This compound improved glucose tolerance from an oral dose of 3 mg/kg and did not change fasting euglycemia even at an oral dose of 30 mg/kg. Selective improvement of glucose-induced insulin secretion was observed in studies using neonatal streptozotocin rats (nSTZ rats) and perfused pancreases isolated from nSTZ rats.
- Published
- 2010
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