26 results on '"Yasuyoshi Arikawa"'
Search Results
2. Abstract 5485: Discovery and preclinical evaluation of a novel highly selective and potent CDK12 inhibitor
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Hiroko Yamakawa, Akio Mizutani, Yasuyoshi Arikawa, Shunsuke Ebara, Yoshihiko Satoh, and Daisuke Morishita
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Cancer Research ,Oncology - Abstract
Recent research highlights that RNA processing is systematically altered in cancer, demonstrating the pivotal influence of RNA deregulation on tumorigenesis, growth and progression. Based on our expanding knowledge of RNA biology, RNA deregulation has drawn much attention from the perspective of cancer therapy. Indeed, small molecules that attack the RNA maturation processes and produce aberrant RNA are currently under development. The first step in gene expression is transcription, which involves copying a DNA sequence to make an RNA. Transcription is performed by enzymes called RNA polymerase (Pol II) that links nucleotides to form RNA strand. The C-terminal domain (CTD) of Pol II comprises heptapeptide Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 repeats and is dynamically post-translationally phosphorylated to regulate the distinct stages of transcription initiation, elongation and termination steps. Particularly, Ser2 and Ser5 phosphorylation have the closest association with the regulation of transcription. Therefore, we focus on the kinases that carry out this modification. Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases. CDK12 regulates the elongation step of RNA transcription by phosphorylation of Ser2 on the CTD. CDK12 complexes with cyclin K to promote the elongation of transcripts, such as BRCA1 and BRCA2, involved in DNA damage responses. It is expected that the inhibition of CDK12 have a synergistic effect with PARP inhibitors and chemotherapeutic reagents. Here we present data on CRD-1835439, orally available, selective, and first in class CDK12 inhibitor with optimized drug-properties. Biochemically, CRD-1835439 is more than 300-fold selective over other CDK isoforms such as CDK7 and CDK9. Importantly, cell based assays showed CRD-1835439 has selective inhibitory activity for phosphorylation of Ser2 on the CTD but not for other Ser5 and Ser7 phosphorylation. Comprehensive analysis by PolyA-seq, Chip-seq and RNA-seq revealed that CRD-1835439 inhibits transcriptional elongation on DNA damage response genes including BRCA1 and BRCA2. The effects on DNA damage and repair were assessed by immunofluorescence staining for γH2AX and RAD51 proteins. In vivo, oral treatment with CRD-1835439 in cell line derived xenograft models, resulted in increase of DNA damage biomarkers, induction of apoptosis and tumor regressions in a dose-dependent fashion. Besides the efficacy as a single reagent, the efficacy was augmented when CRD-1835439 was combined with PARP inhibitors in in vitro and in vivo. In summary, the novel small-molecule CDK12 inhibitor CRD-1835439 demonstrated preclinical efficacy along with target engagement. Our results underscore the preclinical therapeutic potential of CRD-1835439 as a single-agent or in combination with PARP inhibitors for the treatment of intractable cancers. Citation Format: Hiroko Yamakawa, Akio Mizutani, Yasuyoshi Arikawa, Shunsuke Ebara, Yoshihiko Satoh, Daisuke Morishita. Discovery and preclinical evaluation of a novel highly selective and potent CDK12 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5485.
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- 2022
3. Preclinical Evaluation of a Novel MALT1 Inhibitor CTX-177 for Relapse/Refractory Lymphomas
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Akinori Yoda, Seishi Ogawa, Yosuke Minami, Keisuke Kataoka, Kotaro Shide, Kazuya Shimoda, Yasuyoshi Arikawa, Koji Izutsu, Ayako Kamiunten, Akio Mizutani, Daisuke Morishita, Hiroshi Miyake, Yotaro Ochi, Hirokazu Tozaki, and Takuro Kameda
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MALT1 ,Refractory ,business.industry ,Immunology ,Cancer research ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry ,health care economics and organizations - Abstract
Among various subtypes of malignant lymphomas, activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), and adult T-cell leukemia/lymphoma (ATL) are clinically intractable as patients with these lymphomas carry a dismal prognosis, with long-term survival rates of 10-30%. Therefore, a novel therapeutic strategy is required to better manage patients with these malignancies. Recently, we and other investigators performed comprehensive genetic studies and revealed frequent genetic alterations in B and T cell antigen receptor signaling and NF-κB pathway, such as CD79A/B and CARD11 mutations in ABC-DLBCL and PLCG1, PRKCB, and CARD11 mutations in ATL, suggesting the biological relevance of this pathway. To exploit a new treatment strategy in these malignant lymphomas, we focused on the protease mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) which is a key regulator of the antigen receptor signaling and NF-κB pathway and forms a complex with CARD11 and BCL10, and developed a novel compound CTX-177 to inhibit MALT1 with high potency and specificity. CTX-177 was efficacious against ABC-DLBCL and MCL models in vitro and in vivo. Moreover, CTX-177 exhibited combination synergistic effect with BTK inhibitor. In addition, the MALT1 inhibitor showed an anti-tumor effect against CARD11 mutated ABC-DLBCL model, which is resistant to BTK inhibitor. To further explore efficacy of CTX-177 against malignant lymphomas, we generated animal models such as genetically engineered mice and patient-derived xenograft models recapitulating molecular features of these diseases, and examined the response to the MALT1 inhibitor. In these experiments, target engagement of CTX-177 was confirmed by detecting digested substrates of MALT1, and mode of action was evaluated by downregulation of oncogenic transcriptional factor IRF4 which is critical for lymphoma survival. Importantly, the relationship of susceptibility to MALT1 inhibition and gene mutations was analyzed to identity a patient selection biomarker for CTX-177. In summary, the novel, selective, small-molecule MALT1 inhibitor CTX-177 demonstrated preclinical efficacy along with target engagement in several lymphoma models with activated antigen receptor signaling and NF-κB pathway. Our results underscore the preclinical therapeutic potential of CTX-177 as a single-agent or in combination with other inhibitors like BTK inhibitor for the treatment of malignant lymphomas. Disclosures Morishita: Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Mizutani:Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Tozaki:Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Arikawa:Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Kataoka:CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Genomics: Current equity holder in private company. Yoda:Chordia Therapeutics Inc.: Research Funding. Izutsu:Symbio: Research Funding; Solasia: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Novartis: Research Funding; Ono Pharmaceutical: Research Funding; Bayer pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; AstraZeneca: Research Funding; Eisai: Research Funding; Incyte: Research Funding; Abbvie pharmaceuticals: Research Funding; HUYA Japan: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Yakult: Research Funding. Minami:Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria. Shimoda:Otsuka Pharmaceutical: Research Funding; Pfizer Inc.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Merck & Co.: Research Funding; Astellas Pharma: Research Funding; AbbVie Inc.: Research Funding; PharmaEssentia Japan: Research Funding; Perseus Proteomics: Research Funding; Celgene: Honoraria; Shire plc: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Company: Honoraria; Novartis: Honoraria, Research Funding; Asahi Kasei Medical: Research Funding; Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding. Miyake:Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Ogawa:KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding.
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- 2020
4. A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced–Obese Rats With Circadian Rhythm Change
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Shoki Okuda, Yasuyoshi Arikawa, Tomohiro Okawa, Junichi Sakamoto, Nobuyuki Amano, Shinobu Sasaki, Masanori Nakakariya, Yugo Habata, Shizuo Kasai, Natsu Hotta, Kenichi Hamagami, Masaaki Funata, Yasutaka Nagisa, Minoru Maruyama, Toshimi Nagi, and Yasunori Nio
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Male ,0301 basic medicine ,Agonist ,Hypothalamo-Hypophyseal System ,endocrine system ,Sympathetic nervous system ,medicine.medical_specialty ,medicine.drug_class ,Pituitary-Adrenal System ,Diet, High-Fat ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Weight Loss ,medicine ,Animals ,Obesity ,Circadian rhythm ,business.industry ,Suprachiasmatic nucleus ,Body Weight ,Lipid Metabolism ,Rats, Inbred F344 ,Circadian Rhythm ,Rats ,Receptors, Bombesin ,030104 developmental biology ,medicine.anatomical_structure ,Hypothalamus ,Anorectic ,Bombesin Receptor Subtype-3 ,Anti-Obesity Agents ,Corticosterone ,Energy Metabolism ,business ,Diet-induced obese ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
Bombesin receptor subtype 3 (BRS-3) is an orphan G protein-coupled receptor. Based on the obese phenotype of male BRS-3-deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a selective BRS-3 agonist (compound-A) and evaluated its antiobesity effects. Compound-A showed anorectic effects and enhanced energy expenditure in diet-induced-obese (DIO)-F344 rats. Moreover, repeated oral administration of compound-A for 7 days resulted in a significant body weight reduction in DIO-F344 rats. We also evaluated compound-A for cardiovascular side effects using telemeterized Sprague-Dawley (SD) rats. Oral administration of compound-A resulted in transient blood pressure increases in SD rats. To investigate the underlying mechanisms of BRS-3 agonist effects, we focused on the suprachiasmatic nucleus (SCN), the main control center of circadian rhythms in the hypothalamus, also regulating sympathetic nervous system. Compound-A significantly increased the messenger RNA expression of Brs-3, c-fos, and circadian rhythm genes in SCN of DIO-F344 rats. Because SCN also controls the hypothalamic-pituitary-adrenal (HPA) axis, we evaluated the relationship between BRS-3 and the HPA axis. Oral administration of compound-A caused a significant increase of plasma corticosterone levels in DIO-F344 rats. On this basis, energy expenditure enhancement by compound-A may be due to a circadian rhythm change in central and peripheral tissues, enhancement of peripheral lipid metabolism, and stimulation of the sympathetic nervous system. Furthermore, the blood pressure increase by compound-A could be associated with sympathetic nervous system stimulation via SCN and elevation of plasma corticosterone levels through activation of the HPA axis.
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- 2017
5. Bombesin receptor subtype‐3‐expressing neurons regulate energy homeostasis through a novel neuronal pathway in the hypothalamus
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Mayumi Nishida, Natsu Hotta, Kenichi Hamagami, Masaaki Mori, Nobuyuki Amano, Masaaki Funata, Tomohiro Okawa, Shinobu Sasaki, Yasunori Nio, Junichi Sakamoto, Yasutaka Nagisa, Masanori Nakakariya, Yasuyoshi Arikawa, Minoru Maruyama, Toshimi Nagi, Shizuo Kasai, and Yugo Habata
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0301 basic medicine ,Agonist ,Male ,medicine.medical_specialty ,obesity ,medicine.drug_class ,Hypothalamus ,Nerve Tissue Proteins ,CHO Cells ,Biology ,Energy homeostasis ,Rats, Sprague-Dawley ,03 medical and health sciences ,Behavioral Neuroscience ,bombesin receptor subtype‐3 ,Eating ,Cricetulus ,Internal medicine ,medicine ,Animals ,Homeostasis ,Receptors, Somatostatin ,Dorsomedial hypothalamic nucleus ,energy homeostasis ,Original Research ,Mice, Knockout ,Neurons ,fungi ,Feeding Behavior ,Thermoregulation ,Bombesin receptor ,Rats ,Receptors, Bombesin ,030104 developmental biology ,Endocrinology ,nervous system ,neuronal pathway ,Bombesin Receptor Subtype-3 ,Energy Metabolism ,Immunostaining - Abstract
Objectives Bombesin receptor subtype‐3 (BRS‐3) has been suggested to play a potential role in energy homeostasis. However, the physiological mechanism of BRS‐3 on energy homeostasis remains unknown. Thus, we investigated the BRS‐3‐mediated neuronal pathway involved in food intake and energy expenditure. Materials and Methods Expression of BRS‐3 in the rat brain was histologically examined. The BRS‐3 neurons activated by refeeding‐induced satiety or a BRS‐3 agonist were identified by c‐Fos immunostaining. We also analyzed expression changes in feeding‐relating peptides in the brain of fasted rats administered with the BRS‐3 agonist. Results In the paraventricular hypothalamic nucleus (PVH), dorsomedial hypothalamic nucleus (DMH), and medial preoptic area (MPA), strong c‐Fos induction was observed in the BRS‐3 neurons especially in PVH after refeeding. However, the BRS‐3 neurons in the PVH did not express feeding‐regulating peptides, while the BRS‐3 agonist administration induced c‐Fos expression in the DMH and MPA, which were not refeeding‐sensitive, as well as in the PVH. The BRS‐3 agonist administration changed the Pomc and Cart mRNA level in several brain regions of fasted rats. Conclusion These results suggest that BRS‐3 neurons in the PVH are a novel functional subdivision in the PVH that regulates feeding behavior. As the MPA and DMH are reportedly involved in thermoregulation and energy metabolism, the BRS‐3 neurons in the MPA/DMH might mediate the energy expenditure control. POMC and CART may contribute to BRS‐3 neuron‐mediated energy homeostasis regulation. In summary, BRS‐3‐expressing neurons could regulate energy homeostasis through a novel neuronal pathway.
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- 2017
6. Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion
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Hideo Fukui, Ikuo Fujimori, Nobuhiro Inatomi, Koji Ono, Keizo Hirase, Haruyuki Nishida, Akio Imanishi, Yasuyoshi Arikawa, Fumio Itoh, Yasunobu Hori, Jun Matsukawa, Kazuo Nakai, and Yasushi Fujioka
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Drug ,Male ,Stereochemistry ,Potassium ,media_common.quotation_subject ,Clinical Biochemistry ,Pharmaceutical Science ,chemistry.chemical_element ,Administration, Oral ,Ring (chemistry) ,01 natural sciences ,Biochemistry ,Gastric Acid ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,H(+)-K(+)-Exchanging ATPase ,Structure-Activity Relationship ,0302 clinical medicine ,Drug Discovery ,Animals ,Humans ,Pyrroles ,Molecular Biology ,Pyrrole ,media_common ,Sulfonyl ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Proton Pump Inhibitors ,Combinatorial chemistry ,0104 chemical sciences ,Rats ,chemistry ,Molecular Medicine ,Gastric acid ,030211 gastroenterology & hepatology ,Lead compound ,Derivative (chemistry) - Abstract
With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j , which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger C log P value (1.95), larger log D value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a , compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action.
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- 2017
7. Identification of a novel fluoropyrrole derivative as a potassium-competitive acid blocker with long duration of action
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Yasuyoshi Arikawa, Yasushi Fujioka, Motoo Iida, Mitsuyoshi Nishitani, Jun Matsukawa, Toshihiro Imaeda, Teruki Hamada, Yasunobu Hori, Fumio Itoh, Keizo Hirase, Nobuhiro Inatomi, Akio Imanishi, Haruyuki Nishida, Hideo Fukui, and Masahiro Kajino
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0301 basic medicine ,Drug ,Stereochemistry ,Cell Survival ,media_common.quotation_subject ,Potassium ,Clinical Biochemistry ,Lansoprazole ,Pharmaceutical Science ,chemistry.chemical_element ,Administration, Oral ,Biochemistry ,PH elevation ,Gastric Acid ,03 medical and health sciences ,chemistry.chemical_compound ,H(+)-K(+)-Exchanging ATPase ,Structure-Activity Relationship ,Dogs ,Drug Discovery ,medicine ,Animals ,Humans ,Pyrroles ,Molecular Biology ,Pyrrole ,media_common ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Proton Pump Inhibitors ,Hep G2 Cells ,Hydrogen-Ion Concentration ,Combinatorial chemistry ,Ether-A-Go-Go Potassium Channels ,Rats ,030104 developmental biology ,HEK293 Cells ,chemistry ,Lipophilicity ,Molecular Medicine ,Lead compound ,Derivative (chemistry) ,medicine.drug - Abstract
With the aim to find a novel long-lasting potassium-competitive acid blocker (P-CAB) that would perfectly overcome the limitations of proton pump inhibitors (PPIs), we tried various approaches based on pyrrole derivative 1b as a lead compound. As part of a comprehensive approach to identification of a new drug, we explored excellent compounds that have low lipophilicity by introducing a polar hetero-aromatic group at position 5 of the pyrrole ring. Among the compounds synthesized, fluoropyrrole derivative 37c, which has a 2-F-3-Py group at the fifth position, lower pKa, and much lower ClogP and logD values than 1b dose, showed potent gastric-acid suppressive action resulting from gastric H+,K+-ATPase inhibition in animal models. Its maximum intragastric pH elevation effect was strong in rats, and its duration of action was much longer than that of either lansoprazole or lead compound 1b in dogs. Therefore, compound 37c can be considered a promising new P-CAB with long duration of action.
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- 2017
8. Molecular Modeling, Design, Synthesis, and Biological Activity of 1H-Pyrrolo[2,3-c]pyridine-7-amine Derivatives as Potassium-Competitive Acid Blockers
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Makiko Kawamoto, Fumihiko Sato, Atsushi Hasuoka, Nobuhiro Inatomi, Yasuyoshi Arikawa, Terufumi Takagi, Yasunobu Hori, Masahiro Kajino, Naoki Tarui, and Keizo Hirase
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Molecular model ,Stereochemistry ,fungi ,Substituent ,food and beverages ,Biological activity ,General Chemistry ,General Medicine ,In vitro ,chemistry.chemical_compound ,chemistry ,In vivo ,Docking (molecular) ,Drug Discovery ,Pyridine ,Structure–activity relationship - Abstract
A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.
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- 2014
9. Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK)
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Yasuyoshi Arikawa, Pamela Farrell, Betty Lam, Lihong Shi, Zhe Nie, Jones Benjamin, Jonathan Zalevsky, Takahashi Masashi, Victoria A. Feher, Isaac Hoffman, Joshua Cramlett, Corey Wyrick, Hiroshi Miyake, Jennifer Matuszkiewicz, Joanne Miura, Ron de Jong, Charles E. Grimshaw, Jason Yano, Qing Dong, Srinivasa Reddy Natala, Ewan Taylor, and Andrew John Jennings
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0301 basic medicine ,Clinical Biochemistry ,Pharmaceutical Science ,Syk ,Antineoplastic Agents ,Biochemistry ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,0302 clinical medicine ,Mediator ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Syk Kinase ,Molecular Biology ,Protein Kinase Inhibitors ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Drug discovery ,Cell growth ,Organic Chemistry ,Neoplasms, Experimental ,medicine.disease ,Pyrrolidinones ,Lymphoma ,Mice, Inbred C57BL ,Haematopoiesis ,Leukemia ,030104 developmental biology ,Pyrimidines ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Nivolumab ,Drug Screening Assays, Antitumor - Abstract
Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
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- 2016
10. Discovery, synthesis, and biological evaluation of novel pyrrole derivatives as highly selective potassium-competitive acid blockers
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Mitsuyo Kondo, Haruyuki Nishida, Akio Imanishi, Naoki Tarui, Osamu Kurasawa, Masahiro Kajino, Atsushi Hasuoka, Terufumi Takagi, Yasunobu Hori, Nobuhiro Inatomi, Yasuyoshi Arikawa, Fumihiko Sato, and Keizo Hirase
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Male ,Models, Molecular ,Swine ,Stereochemistry ,Potassium ,Clinical Biochemistry ,Pharmaceutical Science ,chemistry.chemical_element ,Inhibitory postsynaptic potential ,Biochemistry ,Pyrrole derivatives ,Rats, Sprague-Dawley ,H(+)-K(+)-Exchanging ATPase ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,Drug Discovery ,Animals ,Structure–activity relationship ,Pyrroles ,Secretion ,Molecular Biology ,Pyrrole ,Molecular Structure ,Drug discovery ,Stomach ,Organic Chemistry ,Proton Pump Inhibitors ,Rats ,chemistry ,Molecular Medicine ,Gastric acid - Abstract
To discover a gastric antisecretory agent more potent than existing proton pump inhibitors, novel pyrrole derivatives were synthesized, and their H(+),K(+)-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 17a exhibited selective and potent H(+),K(+)-ATPase inhibitory activity through reversible and K(+)-competitive ionic binding; furthermore, compound 17c exhibited potent inhibitory action on histamine-stimulated gastric acid secretion in rats and Heidenhain pouch dogs.
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- 2012
11. Discovery of a Novel Pyrrole Derivative 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Fumarate (TAK-438) as a Potassium-Competitive Acid Blocker (P-CAB)
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Atsushi Hasuoka, Mitsuyo Kondo, Haruyuki Nishida, Yasuyoshi Arikawa, Terufumi Takagi, Akio Imanishi, Nobuhiro Inatomi, Osamu Kurasawa, Yasunobu Hori, Keizo Hirase, Masahiro Kajino, Naoki Tarui, Teruki Hamada, Jun Matsukawa, and Toshiyuki Takeuchi
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Male ,Peptic Ulcer ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Potassium ,chemistry.chemical_element ,Pyrrole derivatives ,Rats, Sprague-Dawley ,H(+)-K(+)-Exchanging ATPase ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Dogs ,Fumarates ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Pyrroles ,Enzyme Inhibitors ,Sulfonamides ,Molecular Structure ,Chemistry ,Drug candidate ,Proton Pump Inhibitors ,Nuclear magnetic resonance spectroscopy ,Anti-Ulcer Agents ,medicine.disease ,Rats ,Gastric Mucosa ,Peptic ulcer ,Molecular Medicine ,Gastric acid - Abstract
In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log D and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound 13e exhibited potent H(+),K(+)-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound 13e (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases.
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- 2012
12. Synthetic studies of five-membered heteroaromatic derivatives as potassium-competitive acid blockers (P-CABs)
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Makiko Kawamoto, Yasuyoshi Arikawa, Masahiro Kajino, Fumio Itoh, Naoki Tarui, Atsushi Hasuoka, Nobuhiro Inatomi, Keizo Hirase, Akio Imanishi, Terufumi Takagi, and Haruyuki Nishida
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Stereochemistry ,ATPase ,Potassium ,Clinical Biochemistry ,Molecular Conformation ,Pharmaceutical Science ,chemistry.chemical_element ,Ring (chemistry) ,Biochemistry ,Hydrocarbons, Aromatic ,H(+)-K(+)-Exchanging ATPase ,Inhibitory Concentration 50 ,Heterocyclic Compounds ,Drug Discovery ,Side chain ,Moiety ,Potency ,Molecular Biology ,Lone pair ,biology ,Molecular Structure ,Chemistry ,Organic Chemistry ,In vitro ,biology.protein ,Molecular Medicine - Abstract
On the basis of a series of novel and potent potassium-competitive acid blockers represented by 1-sulfonylpyrrole derivative 7 , we prepared several five-membered heterocyclic analogues ( 8 ) and evaluated their H + ,K + -ATPase activities in vitro. We also assessed the role of the methylaminomethyl side chain by comparison with methylamino and ethylamino derivatives. We observed that the five-membered core ring and its orientation affect inhibitory activity and that the methylaminomethyl moiety is the best side chain. On the basis of potency and ligand-lipophilicity efficiency, compound 7 remains the most drug-like of the compounds studied to date. This study revealed the factors necessary for potent H + ,K + -ATPase inhibition, such as differences in electron density, the properties of the lone pair at each apical position of the heteroaromatic ring, and the geometry of the substituents.
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- 2014
13. Molecular modeling, design, synthesis, and biological activity of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives as potassium-competitive acid blockers
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Yasuyoshi, Arikawa, Atsushi, Hasuoka, Keizo, Hirase, Nobuhiro, Inatomi, Fumihiko, Sato, Yasunobu, Hori, Terufumi, Takagi, Naoki, Tarui, Makiko, Kawamoto, and Masahiro, Kajino
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Male ,Models, Molecular ,Pyridines ,Chemistry, Pharmaceutical ,Drug Evaluation, Preclinical ,Proton Pump Inhibitors ,Rats ,Gastric Acid ,Rats, Sprague-Dawley ,H(+)-K(+)-Exchanging ATPase ,Structure-Activity Relationship ,Drug Design ,Potassium ,Animals ,Histamine - Abstract
A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.
- Published
- 2014
14. Rhodium(I)-, iridium(I)-, and ruthenium(II)-catalyzed asymmetric transfer hydrogenation of ketones using diferrocenyl dichalcogenides as chiral ligands
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Jai Deo Singh, Masanobu Hidai, Yasuyoshi Arikawa, Sakae Uemura, and Yoshiaki Nishibayashi
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Aryl ,Organic Chemistry ,chemistry.chemical_element ,Transfer hydrogenation ,Biochemistry ,Medicinal chemistry ,Ruthenium ,Catalysis ,Rhodium ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Materials Chemistry ,Organic chemistry ,Deuterated methanol ,Physical and Theoretical Chemistry ,Enantiomeric excess ,Chirality (chemistry) - Abstract
[R,S;R,S]-Bis[2-[1-(dimethylamino)ethyl]ferrocenyl] dichalcogenides. (R,S)-{[EC5H3CHMe(NMe2)]Fe(C5H5)}2 (ES, Se, Te), act as chiral ligands for Rh(I)-catalyzed asymmetric transfer hydrogenation of alkyl aryl ketones using a diphenylsilane/methanol system to give the corresponding alcohols in fair to good yields with moderate enantiomeric excess (22–95% ee). The transfer of hydrogen from methanol to the resultant alcohol is confirmed by experiment using deuterated methanol (MeOD), and a new catalytic system containing Rh-hydride species is proposed. In the well-known 2-propanol/base system, the stereoselection is not satisfactory for Rh(I)-, h(I)- and Ru(II)-catalyzed reactions using these ligands.
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- 1997
15. ChemInform Abstract: Enantioselective ortho-Lithiation of Substituted Ferrocenes
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Sakae Uemura, Yoshiaki Nishibayashi, Kouichi Ohe, and Yasuyoshi Arikawa
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Chemistry ,Enantioselective synthesis ,Organic chemistry ,General Medicine - Published
- 2010
16. ChemInform Abstract: Rhodium(I)-, Iridium(I)-, and Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation of Ketones Using Diferrocenyl Dichalcogenides as Chiral Ligands
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Jai Deo Singh, Yasuyoshi Arikawa, Yoshiaki Nishibayashi, Sakae Uemura, and Masanobu Hidai
- Subjects
chemistry.chemical_compound ,Chemistry ,Aryl ,chemistry.chemical_element ,Deuterated methanol ,General Medicine ,Methanol ,Enantiomeric excess ,Transfer hydrogenation ,Medicinal chemistry ,Rhodium ,Ruthenium ,Catalysis - Abstract
[R,S;R,S]-Bis[2-[1-(dimethylamino)ethyl]ferrocenyl] dichalcogenides. (R,S)-{[EC5H3CHMe(NMe2)]Fe(C5H5)}2 (ES, Se, Te), act as chiral ligands for Rh(I)-catalyzed asymmetric transfer hydrogenation of alkyl aryl ketones using a diphenylsilane/methanol system to give the corresponding alcohols in fair to good yields with moderate enantiomeric excess (22–95% ee). The transfer of hydrogen from methanol to the resultant alcohol is confirmed by experiment using deuterated methanol (MeOD), and a new catalytic system containing Rh-hydride species is proposed. In the well-known 2-propanol/base system, the stereoselection is not satisfactory for Rh(I)-, h(I)- and Ru(II)-catalyzed reactions using these ligands.
- Published
- 2010
17. 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases
- Author
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Yasuhiro Tsukimi, Yasunobu Hori, Nobuhiro Inatomi, Keizo Hirase, Jun Matsukawa, Masahiro Kajino, Akio Imanishi, Haruyuki Nishida, and Yasuyoshi Arikawa
- Subjects
Male ,Vonoprazan ,Swine ,Potassium ,Lansoprazole ,chemistry.chemical_element ,Pharmacology ,In Vitro Techniques ,Inhibitory postsynaptic potential ,2-Pyridinylmethylsulfinylbenzimidazoles ,Gastric Acid ,Rats, Sprague-Dawley ,medicine ,Animals ,Secretion ,Pyrroles ,Ligation ,Pylorus ,Sulfonamides ,Stomach ,Imidazoles ,Free base ,Proton Pump Inhibitors ,Hydrogen-Ion Concentration ,Rats ,Dithiothreitol ,Kinetics ,chemistry ,Gastric Mucosa ,Microsome ,Molecular Medicine ,Gastric acid ,medicine.drug ,Histamine - Abstract
Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases. However, several unmet medical needs, such as suppression of night-time acid secretion and rapid symptom relief, remain. In this study, we investigated the pharmacological effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl]- N -methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker (P-CAB), on gastric acid secretion in comparison with lansoprazole, a typical PPI, and SCH28080 [3-(cyanomethyl)-2-methyl,8-(phenylmethoxy)imidazo(1,2- a )pyridine], a prototype of P-CAB. TAK-438, SCH28080, and lansoprazole inhibited H + ,K + -ATPase activity in porcine gastric microsomes with IC 50 values of 0.019, 0.14, and 7.6 μM, respectively, at pH 6.5. The inhibitory activity of TAK-438 was unaffected by ambient pH, whereas the inhibitory activities of SCH28080 and lansoprazole were weaker at pH 7.5. The inhibition by TAK-438 and SCH28080 was reversible and achieved in a K + -competitive manner, quite different from that by lansoprazole. TAK-438, at a dose of 4 mg/kg (as the free base) orally, completely inhibited basal and 2-deoxy-d-glucose-stimulated gastric acid secretion in rats, and its effect on both was stronger than that of lansoprazole. TAK-438 increased the pH of gastric perfusate to a higher value than did lansoprazole or SCH28080, and the effect of TAK-438 was sustained longer than that of lansoprazole or SCH28080. These results indicate that TAK-438 exerts a more potent and longer-lasting inhibitory action on gastric acid secretion than either lansoprazole or SCH28080. TAK-438 is a novel antisecretory drug that may provide a new option for the patients with acid-related disease that is refractory to, or inadequately controlled by, treatment with PPIs.
- Published
- 2010
18. ChemInform Abstract: Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation of Ketones Using Chiral Oxazolinylferrocenylphosphines and One of Their Ru(II) Complex
- Author
-
Masanobu Hidai, Yasuyoshi Arikawa, Kazutaka Matoba, Sakae Uemura, Yoshiaki Nishibayashi, and Masanao Ueoka
- Subjects
inorganic chemicals ,chemistry.chemical_classification ,Chemistry ,organic chemicals ,Aryl ,chemistry.chemical_element ,General Medicine ,Transfer hydrogenation ,Medicinal chemistry ,Catalysis ,Ruthenium ,chemistry.chemical_compound ,Yield (chemistry) ,Organic chemistry ,heterocyclic compounds ,Enantiomeric excess ,Alkyl - Abstract
Chiral oxazolinylferrocenylphosphines act as efficient ligands for Ru(II)-catalyzed asymmetric transfer hydrogenation of a variety of alkyl aryl ketones and alkyl methyl ketones to give the corresponding alcohols in moderate yield with moderate-to-good enantiomeric excess. A new ruthenium(II) complex containing a chiral oxazolinylferrocenylphosphine has been prepared and fully characterized by X-ray crystallography, the complex being revealed to work as a catalyst for this hydrogenation as well.
- Published
- 2010
19. ChemInform Abstract: Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3Antagonists
- Author
-
Shigenori Ohkawa, Yasuyoshi Arikawa, Tatsumi Matsumoto, Keiko Uga, Seiji Miwatashi, Naoyuki Kanzaki, and Yumi N. Imai
- Subjects
Chemistry ,Antagonist ,General Medicine ,Pharmacology ,Adenosine A3 receptor ,Adenosine ,Extravasation ,chemistry.chemical_compound ,medicine ,Potency ,Receptor ,Thiazole ,Acetylcholine ,medicine.drug - Abstract
To investigate the potency of an adenosine A3 receptor (A3AR) antagonist as an anti-asthmatic drug, a novel series of 4-phenyl-5-pyridyl-1,3-thiazole derivatives was synthesized and evaluated in human adenosine A1, A2A and A3 receptor and rat adenosine A3 receptor binding assays. From investigation of the SAR study, compound 7af was identified as a highly potent human and rat A3AR antagonist. This compound inhibited IB-MECA-induced plasma protein extravasation in the skin of rats and showed good oral absorption. Also, compound 7af significantly inhibited antigen-induced hyper-responsiveness to acetylcholine in actively sensitized Brown Norway rats. These results show that 4-phenyl-5-pyridyl-1,3-thiazole derivatives are potential candidates to enable the evaluation of A3AR antagonists. Further evaluation of this class of compounds may afford a novel anti-inflammatory agent such as an anti-asthmatic drug.
- Published
- 2009
20. Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as selective adenosine A3 antagonists
- Author
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Tatsumi Matsumoto, Yasuyoshi Arikawa, Seiji Miwatashi, Keiko Uga, Naoyuki Kanzaki, Shigenori Ohkawa, and Yumi N. Imai
- Subjects
Antagonist ,Adenosine A3 Receptor Antagonists ,General Chemistry ,General Medicine ,Pharmacology ,Adenosine A3 receptor ,Adenosine ,Extravasation ,Rats ,chemistry.chemical_compound ,Structure-Activity Relationship ,Thiazoles ,Biochemistry ,chemistry ,Drug Discovery ,medicine ,Potency ,Animals ,Humans ,Thiazole ,Receptor ,Acetylcholine ,medicine.drug - Abstract
To investigate the potency of an adenosine A3 receptor (A3AR) antagonist as an anti-asthmatic drug, a novel series of 4-phenyl-5-pyridyl-1,3-thiazole derivatives was synthesized and evaluated in human adenosine A1, A2A and A3 receptor and rat adenosine A3 receptor binding assays. From investigation of the SAR study, compound 7af was identified as a highly potent human and rat A3AR antagonist. This compound inhibited IB-MECA-induced plasma protein extravasation in the skin of rats and showed good oral absorption. Also, compound 7af significantly inhibited antigen-induced hyper-responsiveness to acetylcholine in actively sensitized Brown Norway rats. These results show that 4-phenyl-5-pyridyl-1,3-thiazole derivatives are potential candidates to enable the evaluation of A3AR antagonists. Further evaluation of this class of compounds may afford a novel anti-inflammatory agent such as an anti-asthmatic drug.
- Published
- 2008
21. Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent
- Author
-
Seiji Miwatashi, Hiroyuki Kimura, Etsuo Kotani, Maki Miyamoto, Ken-Ichi Naruo, Satoru Asahi, Yasuyoshi Arikawa, Toshimasa Tanaka, and Shigenori Ohkawa
- Subjects
Male ,Models, Molecular ,Arthritis ,Administration, Oral ,Biological Availability ,Pharmacology ,In Vitro Techniques ,p38 Mitogen-Activated Protein Kinases ,Monocytes ,Proinflammatory cytokine ,Cell Line ,Arthritis, Rheumatoid ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Cell Line, Tumor ,Microsomes ,Drug Discovery ,medicine ,Animals ,Cytochrome P-450 CYP3A ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,Protein kinase A ,Benzamide ,IC50 ,biology ,Chemistry ,Tumor Necrosis Factor-alpha ,Cytochrome P450 ,medicine.disease ,Arthritis, Experimental ,Rats ,Isoenzymes ,Thiazoles ,Biochemistry ,Enzyme inhibitor ,Rats, Inbred Lew ,Antirheumatic Agents ,Benzamides ,biology.protein ,Molecular Medicine - Abstract
The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease. To develop a new drug for RA, we synthesized a novel series of 4-phenyl-5-pyridyl-1,3-thiazoles and evaluated their inhibition of p38 MAP kinase, lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells in vitro, and LPS-induced TNF-alpha production in vivo in mice. During the course of the study, we found that these compounds risk the inhibition of cytochrome P450 (CYP) isoforms by coordination of the 4-pyridyl nitrogen with heme iron. We therefore investigated the effects of substitution at the 2-position of the pyridyl ring on the inhibitory activity of p38 MAP kinase and CYPs in more detail. As a result, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (8h, TAK-715) exhibited potent inhibitory activity in these assays (inhibition of p38alpha, IC50 = 7.1 nM; LPS-stimulated release of TNF-alpha from THP-1, IC50 = 48 nM; LPS-induced TNF-alpha production in mice, 87.6% inhibition at 10 mg/kg, po) and no inhibitory activity for major CYPs, including CYP3A4. This compound also showed good bioavailability in mice and rats and significant efficacy in a rat adjuvant-induced arthritis model. Compound 8h was selected as a clinical candidate and is now under clinical investigation for the treatment of RA.
- Published
- 2005
22. Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as p38 MAP kinase inhibitors
- Author
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Shigenori Ohkawa, Hiroyuki Kimura, Ken-Ichi Naruo, Yasuyoshi Arikawa, Keiko Igaki, Seiji Miwatashi, Tomohiro Kawamoto, and Yasumasa Watanabe
- Subjects
Lipopolysaccharides ,Male ,Models, Molecular ,Chemical Phenomena ,Molecular Conformation ,Arthritis ,Pharmacology ,p38 Mitogen-Activated Protein Kinases ,Antibodies ,Proinflammatory cytokine ,Cell Line ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Pharmacokinetics ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Phosphorylation ,Protein kinase A ,Thiazole ,ADME ,Mice, Inbred BALB C ,Chemistry ,Chemistry, Physical ,Tumor Necrosis Factor-alpha ,General Chemistry ,General Medicine ,medicine.disease ,Arthritis, Experimental ,In vitro ,Thiazoles ,Biochemistry ,Collagen - Abstract
A novel series of 4-phenyl-5-pyridyl-1,3-thiazole analogues possessing potent in vitro inhibitory activity against p38 mitogen-activated protein kinase and the release of tumor necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells stimulated by lipopolysaccharide has been identified. Subsequent structure-activity relationship (SAR) studies and optimization for absorption, distribution, metabolism, and elimination (ADME) profiles led to the identification of compounds 7 g and 10b as orally active lead candidates that block the in vivo production of proinflammatory cytokine (TNF-alpha). In pharmacokinetic studies, compound 10b showed good oral administration in mice and demonstrated significant in vivo anti-inflammatory activity in an anti-collagen monoclonal antibody-induced arthritis mouse model (minimum effective dose (MED)=30 mg/kg). Further elucidation of this class of compounds may provide novel anti-inflammatory agents, such as anti-rheumatoid arthritis drugs.
- Published
- 2005
23. W1091 Effects of Tak-438, a Novel Potassium-Competitive Acid Blocker (P-Cab), on Gastric Acid Secretion in Animals
- Author
-
Yasunobu Hori, Haruyuki Nishida, Keizo Hirase, Masahiro Kajino, Yasuhiro Tsukimi, Yasuyoshi Arikawa, Akio Imanishi, Nobuhiro Inatomi, and Jun Matsukawa
- Subjects
medicine.medical_specialty ,Endocrinology ,Hepatology ,Chemistry ,Internal medicine ,Potassium ,Gastroenterology ,medicine ,Gastric acid ,chemistry.chemical_element ,Secretion - Published
- 2010
24. Ruthenium(II)-catalyzed asymmetric transfer hydrogenation of ketones using chiral oxazolinylferrocenylphosphines and one of their Ru(II) complex
- Author
-
Yasuyoshi Arikawa, Sakae Uemura, Kazutaka Matoba, Masanobu Hidai, Yoshiaki Nishibayashi, and Masanao Ueoka
- Subjects
inorganic chemicals ,chemistry.chemical_classification ,organic chemicals ,Aryl ,Organic Chemistry ,chemistry.chemical_element ,Crystal structure ,Transfer hydrogenation ,Biochemistry ,Medicinal chemistry ,Catalysis ,Ruthenium ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Yield (chemistry) ,Materials Chemistry ,heterocyclic compounds ,Physical and Theoretical Chemistry ,Enantiomeric excess ,Alkyl - Abstract
Chiral oxazolinylferrocenylphosphines act as efficient ligands for Ru(II)-catalyzed asymmetric transfer hydrogenation of a variety of alkyl aryl ketones and alkyl methyl ketones to give the corresponding alcohols in moderate yield with moderate-to-good enantiomeric excess. A new ruthenium(II) complex containing a chiral oxazolinylferrocenylphosphine has been prepared and fully characterized by X-ray crystallography, the complex being revealed to work as a catalyst for this hydrogenation as well.
25. Enantioselective ortho-lithiation of substituted ferrocenes
- Author
-
Sakae Uemura, Kouichi Ohe, Yasuyoshi Arikawa, and Yoshiaki Nishibayashi
- Subjects
Chemistry ,Organic Chemistry ,Enantioselective synthesis ,Medicinal chemistry
26. Iridium-catalyzed asymmetric hydrosilylation of imines using chiral oxazolinyl-phosphine ligands
- Author
-
Masanobu Hidai, Sakae Uemura, Yasuyoshi Arikawa, Yoshiaki Nishibayashi, and Izuru Takei
- Subjects
Inorganic Chemistry ,Hydrolysis ,chemistry.chemical_compound ,Chemistry ,Hydrosilylation ,Organic Chemistry ,Polymer chemistry ,chemistry.chemical_element ,Iridium ,Physical and Theoretical Chemistry ,Phosphine ,Catalysis - Abstract
Chiral oxazolinylphosphines are effective ligands for the Ir(I)-catalyzed asymmetric hydrosilylation of imines to afford the corresponding sec-amines with high enantioselectivities (up to 89% ee) after hydrolysis in almost quantitative yields. The structure of an Ir(I)−oxazolinylferrocenylphosphine complex was determined by X-ray analysis.
Catalog
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