Identification of molecular mechanism for actions of NSAID and its application for drug development

2013 Fiscal Year Final Research Report

• Project/Area Number: 24790113
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Shujitsu University (2013); Keio University (2012)
• Principal Investigator: YAMAKAWA Naoki 就実大学, 薬学部, 講師 (20583040)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: 医薬品探索

Research Abstract

In this study, we have examined the gene changing expression frequency after target NSAIDs treatment. As a result, we identified a series of NSAIDs that changed heat shock protein-related genetic expression. As a result of being interesting, we found that carboxylic acid-based NSAIDs greatly changes expression of HSP25 and HSP27. We identified a cytotoxic weak NSAID with superior anti-inflammatory action. However, an expected effect was not provided at the animal level. Therefore we synthesized the derivative of the target NSAID that we identified and discovered new compounds with a few gastric ulcer side effects.

Research Products

• [Journal Article] Superiority of pulmonary administration of mepenzolate bromide over other routes as treatment for chronic obstructive pulmonary disease (2014)
  • Author(s): Tanaka, K., Kurotsu, S., Asano, T., Yamakawa, N., Kobayashi, D., Yamashita, Y., Yamazaki, H., Ishihara, T., Watanabe, H., Maruyama, T., Suzuki, H. and Mizushima, T
  • Journal Title: Sci Rep Volume: 4 Pages: 4510
• [Journal Article] Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity (2014)
  • Author(s): Yamakawa, N., Suzuki, K., Yamashita, Y., Katsu, T., Hanaya, K., Shoji, M., Sugai, T. and Mizushima, T
  • Journal Title: Bioorg Med Chem Volume: 22 Pages: 2529-2534
• [Journal Article] Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities (2014)
  • Author(s): Yamashita, Y., Tanaka, K., Asano, T., Yamakawa, N., Kobayashi, D., Ishihara, T., Hanaya, K., Shoji, M., Sugai, T., Wada, M., Mashimo, T., Fukunishi, Y. and Mizushima, T
  • Journal Title: Bioorg Med Chem Volume: 22 Pages: 3488-3497
• [Journal Article] Suppression of Alzheimer's Disease-Related Phenotypes by Geranylgeranylacetone in Mice (2013)
  • Author(s): Hoshino, T., Suzuki, K., Matsushima, T., Yamakawa, N., Suzuki, T. and Mizushima, T
  • Journal Title: PLoS One Volume: 8 Pages: 76306
• [Journal Article] Prostaglandin E1 -containing nanoparticles improve walking activity in an experimental rat model of intermittent claudication (2013)
  • Author(s): Ishihara, T., Yamashita, Y., Takasaki, N., Yamamoto, S., Hayashi, E., Tahara, K., Takenaga, M., Yamakawa, N., Kasahara, T. and Mizushima, T
  • Journal Title: J Pharm Pharmacol Volume: 65 Pages: 1187-1194
• [Journal Article] Suppression of UV-induced wrinkle formation by induction of HSP70 expression in mice (2013)
  • Author(s): Matsuda, M., Hoshino, T., Yamakawa, N., Tahara, K., Adachi, H., Sobue, G., Maji, D., Ihn, H. and Mizushima, T
  • Journal Title: J Invest Dermatol Volume: 132 Pages: 919-928
• [Journal Article] Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease (2013)
  • Author(s): Tanaka, K., Ishihara, T., Sugizaki, T., Kobayashi, D., Yamashita, Y., Tahara, K., Yamakawa, N., Iijima, K., Mogushi, K., Tanaka, H., Sato, K., Suzuki, H. and Mizushima, T
  • Journal Title: Nat Commun Volume: 4 Pages: 2686
• [Journal Article] Comparison of pharmacokinetics between loxoprofen and its derivative with lower ulcerogenic activity, fluoro-loxoprofen (2013)
  • Author(s): Yamakawa, N., Suemasu, S., Watanabe, H., Tahara, K., Tanaka, K., Okamoto, Y., Ohtsuka, M., Maruyama, T. and Mizushima, T
  • Journal Title: Drug Metab Pharmacokinet Volume: 28 Pages: 118-124
• [Journal Article] Identification of a unique nsaid, fluoro-loxoprofen with gastroprotective activity (2012)
  • Author(s): Suemasu, S., Yamakawa, N., Ishihara, T., Asano, T., Tahara, K., Tanaka, K., Matsui, H., Okamoto, Y., Otsuka, M., Takeuchi, K., Suzuki, H. and Mizushima, T
  • Journal Title: Biochem Pharmacol Volume: 84 Pages: 1470-1481
• [Journal Article] Expression of 150-kDa oxygen-regulated protein (ORP150) stimulates bleomycin-induced pulmonary fibrosis and dysfunction in mice (2012)
  • Author(s): Tanaka, K., Shirai, A., Ito, Y., Namba, T., Tahara, K., Yamakawa, N. and Mizushima, T
  • Journal Title: Biochem Biophys Res Commun Volume: 425 Pages: 818-824
• [Journal Article] Synthesis and Biological Evaluation of Derivatives of 2-{2-Fluoro-4-[(2-oxocyclopentyl)methyl ]phenyl}propanoic Acid : Nonsteroidal Anti-Inflammatory Drugs with Low Gastric Ulcerogenic Activity (2012)
  • Author(s): Yamakawa, N., Suemasu, S., Okamoto, Y., Tanaka, K., Ishihara, T., Asano, T., Miyata, K., Otsuka, M. and Mizushima, T
  • Journal Title: Journal of Medicinal Chemistry Volume: 55 Pages: 5143-5150