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Dive into the research topics where Tomoyuki Kitazaki is active.

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Featured researches published by Tomoyuki Kitazaki.


European Journal of Pharmacology | 2008

TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain

Tomohiro Kawamoto; Masayuki; Tomoyuki Kitazaki; Yuji Iizawa; Hiroyuki Kimura

TAK-242, a small-molecule antisepsis agent, has shown to suppress lipopolysaccharide (LPS)-induced inflammation. In this study, we demonstrate that TAK-242 is a selective inhibitor of Toll-like receptor (TLR)-4 signaling. TAK-242 almost completely suppressed production of nitric oxide (NO) or tumor necrosis factor (TNF)-alpha induced by a TLR4-specific ligand, ultra-pure LPS, in mouse RAW264.7, human U-937 and P31/FUJ cells, whereas this agent showed little effect on other TLR ligands, Pam(3)CSK(4) (TLR1/2), peptidoglycan (TLR2/6), double strand RNA (TLR3), R-848 (TLR7) and CpG oligonucleotide (TLR9). Furthermore, TAK-242 potently inhibited nuclear factor (NF)-kappaB activation induced by ultra-pure LPS in HEK293 cells transiently expressing TLR4 and co-receptors, myeloid differentiation protein-2 (MD2) and CD14, whereas this agent showed little effect on other TLRs, TLR1/2, TLR2/6, TLR3, TLR5, TLR7 and TLR9. TAK-242 also inhibited ligand-independent NF-kappaB activation resulting from over-expression of TLR4. Although chimera receptors, which are consist of the extracellular domain of CD4 and the intracellular domain of human or mouse TLR4, showed constitutive NF-kappaB activation, TAK-242 potently inhibited the signaling from CD4-TLR4 chimera receptors. In contrast, the NF-kappaB activation mediated by TLR4 adaptors, myeloid differentiation factor 88 (MyD88), TIR-associated protein (TIRAP), Toll/IL-1R homology (TIR)-domain-containing adaptor protein-inducing interferon-beta (TRIF) or TRIF-related adaptor molecule (TRAM) was not affected by TAK-242. TAK-242 is therefore a selective inhibitor of signaling from the intracellular domain of TLR4 and represents a novel therapeutic approach to the treatment of TLR4-mediated diseases.


Journal of Medicinal Chemistry | 2015

Discovery of a Novel Series of N-Phenylindoline-5-sulfonamide Derivatives as Potent, Selective, and Orally Bioavailable Acyl CoA:Monoacylglycerol Acyltransferase-2 Inhibitors

Kenjiro Sato; Hiroki Takahagi; Takeshi Yoshikawa; Shinji Morimoto; Takafumi Takai; Kousuke Hidaka; Masahiro Kamaura; Osamu Kubo; Ryutaro Adachi; Tsuyoshi Ishii; Toshiyuki Maki; Taisuke Mochida; Shiro Takekawa; Masanori Nakakariya; Nobuyuki Amano; Tomoyuki Kitazaki

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has attracted interest as a novel target for the treatment of obesity and metabolic diseases. Starting from N-phenylbenzenesulfonamide derivative 1 with moderate potency for MGAT2 inhibition, we explored an effective location of the hydrophobic group at the 1-position to enhance MGAT2 inhibitory activity. Shifting the hydrophobic group to the adjacent position followed by introduction of a bicyclic central core to restrict the substituent orientation produced N-phenylindoline-5-sulfonamide derivative 10b, which displayed much improved potency, with an IC50 value of 1.0 nM. This compound also exhibited excellent selectivity (greater than 30,000-fold) against related acyltransferases (MGAT3, DGAT1, DGAT2, and ACAT1). Subsequent optimization efforts were directed toward improving pharmacokinetic profiles, which resulted in the identification of 5-[(2,4-difluorophenyl)sulfamoyl]-7-(2-oxopyrrolidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indole-1-carboxamide (24d) endowed with potent MGAT2 inhibitory activity (IC50 = 3.4 nM) and high oral bioavailability (F = 52%, mouse). In a mouse oral fat tolerance test, oral administration of this compound effectively suppressed the elevation of plasma triacylglycerol levels.


Chemical & Pharmaceutical Bulletin | 1995

Optically Active Antifungal Azoles. V. Synthesis and Antifungal Activity of Stereoisomers of 3-Azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols

Akihiro Tasaka; Norikazu Tamura; Yoshihiro Matsushita; Tomoyuki Kitazaki; Ryogo Hayashi; Kenji Okonogi; Katsumi Itoh

The (2S,3S)-, (2R,3S)- and (2S,3R)-stereoisomers of (2R,3R)-3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols [(2R,3R)-1a--d] were prepared and evaluated for antifungal activity against Candida albicans in vitro and in vivo to clarify the relationships between stereochemistry and biological activities. The results revealed that the in vitro antifungal activity in each set of the four stereoisomers [(2R,3R)-, (2S,3S)-, (2R,3S)- and (2S,3R)-1a--d] definitely paralleled the in vivo antifungal activity against candidosis in mice, and the order of potency was (2R,3R) >> (2R,3S) > or = (2S,3S) > or = (2S,3R). In addition, the four stereoisomers in each set were assessed for sterol biosynthesis-inhibitory activities in C. albicans and rat liver. The (2R,3R)-isomer was found to exert a strong and selective inhibitory effect on the sterol synthesis in C. albicans as compared with that in rat liver.


Journal of Medicinal Chemistry | 2011

Discovery of 1-{4-[1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a Potent, Orally Active, Non-Peptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor

Kazuhiro Miwa; Takenori Hitaka; Takashi Imada; Satoshi Sasaki; Mie Yoshimatsu; Masami Kusaka; Akira Tanaka; Daisuke Nakata; Shuichi Furuya; Satoshi Endo; Kazumasa Hamamura; Tomoyuki Kitazaki

We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.


Bioorganic & Medicinal Chemistry | 2008

Novel cyclohexene derivatives as anti-sepsis agents : Synthetic studies and inhibition of NO and cytokine production

Masami Yamada; Takashi Ichikawa; Masayuki; Katsumi Itoh; Norikazu Tamura; Tomoyuki Kitazaki

In order to develop an anti-sepsis agent, a series of cyclohexene derivatives were synthesized and evaluated for their biological activities. Through modification of the sulfonamide spacer moiety depicted by formula II, it was found that the benzylsulfone derivative 10a had potent inhibitory activity against the production of NO. Further modifications of the phenyl ring, ester moiety, and benzyl position of benzylsulfone derivatives III were carried out. Among these compounds, (R)-(+)-10a and (6R, 1S)-(+)-22a showed strong inhibitory activity not only against NO production but also against inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in vitro. Furthermore, (R)-(+)-10a and (6R, 1S)-(+)-22a protected mice from LPS-induced lethality in a dose-dependent manner.


Antimicrobial Agents and Chemotherapy | 2002

Efficacy of TAK-457, a Novel Intravenous Triazole, against Invasive Pulmonary Aspergillosis in Neutropenic Mice

Ryogo Hayashi; Naomi Kitamoto; Yuji Iizawa; Takashi Ichikawa; Katsumi Itoh; Tomoyuki Kitazaki; Kenji Okonogi

ABSTRACT TAK-457 is an injectable prodrug of TAK-456, which is a novel oral triazole compound with potent antifungal activity. The in vivo efficacy of TAK-457 was evaluated in two models of invasive pulmonary aspergillosis with CDF1 mice and CBA/J mice with transient neutropenia induced by cyclophosphamide. Against the infection in CDF1 mice, treatment with 10 mg of TAK-457 and 1 mg of amphotericin B/kg reduced the fungal burden in lungs and rescued all mice. In the infection model with CBA/J mice, TAK-457 at a dose of 10 mg/kg significantly prolonged the survival time of mice, showing significant reduction of lung chitin levels and the plasma β-d-glucan levels. On the other hand, amphotericin B at 1 mg/kg which was a maximum tolerable dose showed slight but not significant prolongation of survival time of mice, although it also reduced the lung chitin levels and the plasma β-d-glucan levels to a lower extent but still significantly. These results suggest that TAK-457 is a promising candidate for development for the treatment of invasive aspergillosis in humans.


Bioorganic & Medicinal Chemistry | 2015

Optimization of a novel series of N-phenylindoline-5-sulfonamide-based acyl CoA:monoacylglycerol acyltransferase-2 inhibitors: Mitigation of CYP3A4 time-dependent inhibition and phototoxic liabilities

Kenjiro Sato; Hiroki Takahagi; Osamu Kubo; Kousuke Hidaka; Takeshi Yoshikawa; Masahiro Kamaura; Masanori Nakakariya; Nobuyuki Amano; Ryutaro Adachi; Toshiyuki Maki; Kazumi Take; Shiro Takekawa; Tomoyuki Kitazaki; Tsuyoshi Maekawa

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has emerged as a potential peripheral target for the treatment of obesity and metabolic disorders. We previously identified a novel series of N-phenylindoline-5-sulfonamide derivatives exemplified by 2 as potent and orally bioavailable MGAT2 inhibitors. Despite its attractive potency, further assessment revealed that this compound exhibited time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4). To remove the undesirable CYP3A4 TDI activity, structural modification was focused on the 2,4-difluoroaniline moiety on the basis of the assumption that this moiety would be involved in mechanism-based inhibition of CYP3A4 via oxidative metabolism. This led to the finding that the introduction of 4-chloro-2,6-difluoroaniline significantly improved CYP3A4 TDI risk. Further optimization resulted in the discovery of N-(4-chloro-2,6-difluorophenyl)-1-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]pyrimidin-2-yl}-7-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-indole-5-sulfonamide (27c) with potent MGAT2 inhibitory activity (IC50=7.8 nM) and excellent ADME-Tox profiles including metabolic stability, oral bioavailability, and CYP3A4 TDI. In a mouse oral fat tolerance test, compound 27c effectively and dose-dependently suppressed the elevation of plasma triacylglycerol levels after oral administration at doses of 1 and 3mg/kg. We also discuss mitigation of the phototoxic liability of biaryl derivatives on the basis of the HOMO-LUMO gap hypothesis during the course of optimization efforts.


PLOS ONE | 2016

Pharmacological Inhibition of Monoacylglycerol O-Acyltransferase 2 Improves Hyperlipidemia, Obesity, and Diabetes by Change in Intestinal Fat Utilization

Kazumi Take; Taisuke Mochida; Toshiyuki Maki; Yoshinori Satomi; Megumi Hirayama; Masanori Nakakariya; Nobuyuki Amano; Ryutaro Adachi; Kenjiro Sato; Tomoyuki Kitazaki; Shiro Takekawa

Monoacylglycerol O-acyltransferase 2 (MGAT2) catalyzes the synthesis of diacylglycerol (DG), a triacylglycerol precursor and potential peripheral target for novel anti-obesity therapeutics. High-throughput screening identified lead compounds with MGAT2 inhibitory activity. Through structural modification, a potent, selective, and orally bioavailable MGAT2 inhibitor, compound A (compA), was discovered. CompA dose-dependently inhibited postprandial increases in plasma triglyceride (TG) levels. Metabolic flux analysis revealed that compA inhibited triglyceride/diacylglycerol resynthesis in the small intestine and increased free fatty acid and acyl-carnitine with shorter acyl chains than originally labelled fatty acid. CompA decreased high-fat diet (HFD) intake in C57BL/6J mice. MGAT2-null mice showed a similar phenotype as compA-treated mice and compA did not suppress a food intake in MGAT2 KO mice, indicating that the anorectic effects were dependent on MGAT2 inhibition. Chronic administration of compA significantly prevented body weight gain and fat accumulation in mice fed HFD. MGAT2 inhibition by CompA under severe diabetes ameliorated hyperglycemia and fatty liver in HFD-streptozotocin (STZ)-treated mice. Homeostatic model assessments (HOMA-IR) revealed that compA treatment significantly improved insulin sensitivity. The proximal half of the small intestine displayed weight gain following compA treatment. A similar phenomenon has been observed in Roux-en-Y gastric bypass-treated animals and some studies have reported that this intestinal remodeling is essential to the anti-diabetic effects of bariatric surgery. These results clearly demonstrated that MGAT2 inhibition improved dyslipidemia, obesity, and diabetes, suggesting that compA is an effective therapeutic for obesity-related metabolic disorders.


Molecular Pharmacology | 2006

A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling.

Masayuki; Naoko Matsunaga; Kaoru Hazeki; Kazuyo Nakamura; Katsunori Takashima; Tsukasa Seya; Osamu Hazeki; Tomoyuki Kitazaki; Yuji Iizawa


European Journal of Pharmacology | 2007

Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model

Takukyu Sha; Mie Sunamoto; Tomoyuki Kitazaki; Jun Sato; Masayuki; Yuji Iizawa

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Katsumi Itoh

Takeda Pharmaceutical Company

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Masayuki

Takeda Pharmaceutical Company

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Yoshihiro Matsushita

Takeda Pharmaceutical Company

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Yuji Iizawa

Takeda Pharmaceutical Company

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Junji Yamada

Takeda Pharmaceutical Company

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Kenji Okonogi

Takeda Pharmaceutical Company

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Takashi Ichikawa

Takeda Pharmaceutical Company

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Hiroshi Hosono

Takeda Pharmaceutical Company

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Norikazu Tamura

Takeda Pharmaceutical Company

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Yuzo Ichimori

Takeda Pharmaceutical Company

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