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Dive into the research topics where Futoshi Nara is active.

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Featured researches published by Futoshi Nara.


Journal of Biological Chemistry | 1997

The BST1 gene of Saccharomyces cerevisiae is the sphingosine-1-phosphate lyase.

Julie D. Saba; Futoshi Nara; Alicia Bielawska; Steven Garrett; Yusuf A. Hannun

Sphingolipids elicit a wide variety of eukaryotic cellular responses, most involving regulation of cell growth, differentiation, and apoptosis. Sphingosine 1-phosphate, a sphingolipid catabolite, is mitogenic in fibroblasts and inhibits the chemotactic mobility and invasiveness of human tumor cells. Sphingosine 1-phosphate degradation requires cleavage at the C2–3 carbon bond by sphingosine phosphate lyase. A yeast genetic approach was used to clone the first sphingosine phosphate lyase gene, BST1. BST1 overexpression conferred resistance to sphingosine in yeast.BST1 deletion produced sensitivity to exogenousd-erythro-sphingosine and phytosphingosine and intracellular accumulation of sphingosine 1-phosphate upon exposure to exogenous sphingosine. This study confirms that sphingoid base metabolism is similar in all eukaryotes and suggests that yeast genetics may be useful in the isolation and identification of other genes involved in sphingolipid signaling and metabolism.


Journal of Biological Chemistry | 2003

Nerve Growth Factor-induced Glutamate Release Is via p75 Receptor, Ceramide, and Ca2+ from Ryanodine Receptor in Developing Cerebellar Neurons

Tadahiro Numakawa; Hitoshi Nakayama; Shingo Suzuki; Takekazu Kubo; Futoshi Nara; Yumiko Numakawa; Daisaku Yokomaku; Toshiyuki Araki; Tetsuya Ishimoto; Akihiko Ogura; Takahisa Taguchi

Very little is known about the contribution of a low affinity neurotrophin receptor, p75, to neurotransmitter release. Here we show that nerve growth factor (NGF) induced a rapid release of glutamate and an increase of Ca2+ in cerebellar neurons through a p75-dependent pathway. The NGF-induced release occurred even in the presence of the Trk inhibitor K252a. The release caused by NGF but not brain-derived neurotrophic factor was enhanced in neurons overexpressing p75. Further, after transfection of p75-small interfering RNA, which down-regulated the endogenous p75 expression, the NGF-induced release was inhibited, suggesting that the NGF-induced glutamate release was through p75. We found that the NGF-increased Ca2+ was derived from the ryanodine-sensitive Ca2+ receptor and that the NGF-increased Ca2+ was essential for the NGF-induced glutamate release. Furthermore, scyphostatin, a sphingomyelinase inhibitor, blocked the NGF-dependent Ca2+ increase and glutamate release, suggesting that a ceramide produced by sphingomyelinase was required for the NGF-stimulated Ca2+ increase and glutamate release. This action of NGF only occurred in developing neurons whereas the brain-derived neurotrophic factor-mediated Ca2+ increase and glutamate release was observed at the mature neuronal stage. Thus, we demonstrate that NGF-mediated neurotransmitter release via the p75-dependent pathway has an important role in developing neurons.


ACS Medicinal Chemistry Letters | 2011

Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist.

Takahide Nishi; Shojiro Miyazaki; Toshiyasu Takemoto; Keisuke Suzuki; Yukiko Iio; Katsuyoshi Nakajima; Takashi Ohnuki; Yumi Kawase; Futoshi Nara; Shin-ichi Inaba; Takashi Izumi; Hiroshi Yuita; Keiko Oshima; Hiromi Doi; Ryotaku Inoue; Wataru Tomisato; Takashi Kagari; Takaichi Shimozato

CS-0777 (3) is phosphorylated in vivo, and the phosphate of CS-0777 (CS-0777-P) (4) acts as a selective S1P receptor-1 (S1P1) modulator. We report herein the synthesis of CS-0777 and CS-0777-P, pharmacological effects such as S1P1 and S1P3 agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effect on experimental autoimmune encephalomyelitis (EAE), and also the pharmacokinetics in rats. CS-0777-P had ∼320-fold greater agonist activity for human S1P1 (EC50; 1.1 nM) relative to S1P3 (EC50; 350 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-0777 in rats, lymphocyte counts decreased significantly, with a nadir at 12 h postdose and recovery to vehicle control levels by 5 days postdose. In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for the 0.1 and 1 mg/kg CS-0777 groups in rats. CS-0777 is currently in clinical trials for the treatment of multiple sclerosis (MS).


ACS Medicinal Chemistry Letters | 2013

Potent and Orally Bioavailable GPR142 Agonists as Novel Insulin Secretagogues for the Treatment of Type 2 Diabetes

Narihiro Toda; Xiaolin Hao; Yasuyuki Ogawa; Kozo Oda; Ming Yu; Zice Fu; Yi Chen; Yong-Jae Kim; Mike Lizarzaburu; Sarah E. Lively; Shauna Lawlis; Michiko Murakoshi; Futoshi Nara; Nobuaki Watanabe; Jeff D. Reagan; Hui Tian; Angela Fu; Alykhan Motani; Qingxiang Liu; Yi-Jyun Lin; Run Zhuang; Yumei Xiong; Peter Fan; Julio C. Medina; Leping Li; Masanori Izumi; Ryo Okuyama; Satoshi Shibuya

GPR142 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR142 agonists stimulate insulin secretion in the presence of high glucose concentration, so that they could be novel insulin secretagogues with reduced or no risk of hypoglycemia. We report here the optimization of HTS hit compound 1 toward a proof of concept compound 33, which showed potent glucose lowering effects during an oral glucose tolerance test in mice and monkeys.


ACS Medicinal Chemistry Letters | 2013

Aminopyrazole-Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies.

Ming Yu; Mike Lizarzaburu; Alykhan Motani; Zice Fu; Xiaohui Du; Jiwen Liu; Xianyun Jiao; SuJen Lai; Peter Fan; Angela Fu; Qingxiang Liu; Michiko Murakoshi; Futoshi Nara; Kozo Oda; Ryo Okuyama; Jeff D. Reagan; Nobuaki Watanabe; Mami Yamazaki; Yumei Xiong; Ying Zhang; Run Zhuang; Daniel C.-H. Lin; Jonathan B. Houze; Julio C. Medina; Leping Li

Herein, we report the lead optimization of amrinone-phenylalanine based GPR142 agonists. Structure-activity relationship studies led to the discovery of aminopyrazole-phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets.


Journal of Biological Chemistry | 2011

Purification and Identification of Activating Enzymes of CS-0777, a Selective Sphingosine 1-Phosphate Receptor 1 Modulator, in Erythrocytes

Kiyoaki Yonesu; Kazuishi Kubota; Masakazu Tamura; Shin-ichi Inaba; Tomohiro Honda; Chizuko Yahara; Nobuaki Watanabe; Tatsuji Matsuoka; Futoshi Nara

CS-0777 is a selective sphingosine 1-phosphate (S1P) receptor 1 modulator with potential benefits in the treatment of autoimmune diseases, including multiple sclerosis. CS-0777 is a prodrug that requires phosphorylation to an active S1P analog, similar to the first-in-class S1P receptor modulator FTY720 (fingolimod). We sought to identify the kinase(s) involved in phosphorylation of CS-0777, anticipating sphingosine kinase (SPHK) 1 or 2 as likely candidates. Unlike kinase activity for FTY720, which is found predominantly in platelets, CS-0777 kinase activity was found mainly in red blood cells (RBCs). N,N-Dimethylsphingosine, an inhibitor of SPHK1 and -2, did not inhibit CS-0777 kinase activity. We purified CS-0777 kinase activity from human RBCs by more than 10,000-fold using ammonium sulfate precipitation and successive chromatography steps, and we identified fructosamine 3-kinase (FN3K) and fructosamine 3-kinase-related protein (FN3K-RP) by mass spectrometry. Incubation of human RBC lysates with 1-deoxy-1-morpholinofructose, a competitive inhibitor of FN3K, inhibited ∼10% of the kinase activity, suggesting FN3K-RP is the principal kinase responsible for activation of CS-0777 in blood. Lysates from HEK293 cells overexpressing FN3K or FN3K-RP resulted in phosphorylation of CS-0777 and structurally related molecules but showed little kinase activity for FTY720 and no kinase activity for sphingosine. Substrate preference was highly correlated among FN3K, FN3K-RP, and rat RBC lysates. FN3K and FN3K-RP are known to phosphorylate sugar moieties on glycosylated proteins, but this is the first report that these enzymes can phosphorylate hydrophobic xenobiotics. Identification of the kinases responsible for CS-0777 activation will permit a better understanding of the pharmacokinetics and pharmacodynamics of this promising new drug.


Journal of Receptors and Signal Transduction | 2017

Discovery and pharmacological effects of a novel GPR142 antagonist

Michiko Murakoshi; Harumi Kuwabara; Miyuki Nagasaki; Yu Mei Xiong; Jeff D. Reagan; Hiroaki Maeda; Futoshi Nara

Abstract GPR142 is a G-protein-coupled receptor (GPCR), whose most potent and efficacious ligand has been reported as being the natural amino acid l-tryptophan. GPR142 is highly expressed in pancreatic β-cells and immune cells, suggesting the receptor may play a role in the pathogenesis and development of diabetes or inflammatory diseases. In a previous report, we developed GPR142 agonists as insulin secretagogues. In this report, we show the discovery of a selective, potent small-molecule GPR142 antagonist, CLP-3094, and its pharmacological characteristics. These data support targeting this receptor for the treatment of chronic inflammatory diseases.


Archive | 2003

Amino alcohol derivatives

Takahide Nishi; Toshiyasu Takemoto; Takaichi Shimozato; Futoshi Nara


Archive | 2005

Amino alcohol compound

Takahide Nishi; Toshiyasu Takemoto; Shojiro Miyazaki; Takaichi Shimozato; Futoshi Nara; Takashi Izumi


Archive | 2004

Amino alcohol derivatives or phosphonic acid derivatives and pharmaceutical compositions containing these

Takahide Nishi; Takaichi Shimozato; Futoshi Nara; Shojiro Miyazaki

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Takahide Nishi

Tokyo Institute of Technology

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