- ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model
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Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (20), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (20), which enhanced the antitumor effect of paclitaxel in a breast cancer model.
- Hiramatsu, Atsushi,Hirooka, Yasuo,Hisaichi, Katsuya,Imagawa, Akira,Iwaki, Yuzo,Katoh, Makoto,Kobayashi, Juta,Komichi, Yuka,Maeda, Tatsuo,Matsumura, Naoya,Moriguchi, Hideki,Nakatani, Shingo,Nishiyama, Taihei,Ohhata, Akira,Okabe, Yasuyuki,Okada, Masahiro,Ota, Hiroto,Saga, Hiroshi,Sugiyama, Tetsuya,Watanabe, Toshihide,Yamamoto, Shingo
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supporting information
p. 1335 - 1341
(2020/07/06)
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- NOVEL IMIDE DERIVATIVES AND USE THEREOF AS MEDICINE
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Provided is a novel low-molecular-weight compound that suppresses production of induction type MMPs, particularly MMP-9, rather than production of hemostatic type MMP-2. The present invention relates to a compound represented by the following formula (I): wherein each symbol is as described in the DESCRIPTION. The compound has a selective MMP-9 production suppressive action, and is useful as a drug for the prophylaxis and/or treatment of autoimmune diseases such as rheumatoid arthritis and the like, inflammatory bowel diseases (ulcerative colitis, Crohn's disease) or osteoarthritis.
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Paragraph 0152
(2018/05/24)
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- Synthesis and evaluation of a classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as antifolates
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Two classical antifolates, a 2,4-diamino-5-substituted furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine, were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The synthese
- Gangjee, Aleem,Yang, Jie,McGuire, John J.,Kisliuk, Roy L.
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p. 8590 - 8598
(2008/02/08)
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- Synthesis of 2-indanones via [4 + 1] annulation reactions of (trialkylsilyl)arylketenes
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(Matrix presented) (Trialkylsilyl)arylketenes combine with (trimethylsilyl)diazomethane in a new [4 + 1] annulation process leading to 2-indanone derivatives. The (trialkylsilyl)arylketene annulation substrates are available via the photochemical Wolff rearrangement of α-silyl-α-diazo ketones, which are themselves prepared by silylation of the corresponding diazo ketones. The mechanism of the annulation reaction is proposed to involve the formation of a 2,3-bis(silyl)cyclopropanone, which is in equilibrium with an oxyallylic cation. Electrocyclic closure of this intermediate forms the new cyclopentenone ring.
- Dalton, Audra M.,Zhang, Yongjun,Davie, Christopher P.,Danheiser, Rick L.
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p. 2465 - 2468
(2007/10/03)
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- [60]Fullerene as a substituent
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The substituent effect of the dihydro[60]fullerenyl group and its hydrophobic parameters have been evaluated quantitatively. The substituent constant has been determined from the pK value of a fullerene-based, para-substituted benzoic acid 1 in 80% dioxan
- Bagno, Alessandro,Claeson, Sofia,Maggini, Michele,Martini, Maria Luisa,Prato, Maurizio,Scorrano, Gianfranco
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p. 1015 - 1023
(2007/10/03)
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