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Research Article

OPC-67683, a Nitro-Dihydro-Imidazooxazole Derivative with Promising Action against Tuberculosis In Vitro and In Mice

  • Makoto Matsumoto mail,

    To whom correspondence should be addressed. E-mail: m_matsumoto@research.otsuka.co.jp

    Affiliation: Microbiological Research Institute, Otsuka Pharmaceutical, Tokushima, Japan

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  • Hiroyuki Hashizume,

    Affiliation: Microbiological Research Institute, Otsuka Pharmaceutical, Tokushima, Japan

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  • Tatsuo Tomishige,

    Affiliation: Microbiological Research Institute, Otsuka Pharmaceutical, Tokushima, Japan

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  • Masanori Kawasaki,

    Affiliation: Microbiological Research Institute, Otsuka Pharmaceutical, Tokushima, Japan

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  • Hidetsugu Tsubouchi,

    Affiliation: Medicinal Chemistry Research Institute, Otsuka Pharmaceutical, Tokushima, Japan

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  • Hirofumi Sasaki,

    Affiliation: Medicinal Chemistry Research Institute, Otsuka Pharmaceutical, Tokushima, Japan

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  • Yoshihiko Shimokawa,

    Affiliation: Tokushima Research Institute, Otsuka Pharmaceutical, Tokushima, Japan

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  • Makoto Komatsu

    Affiliation: Medicinal Chemistry Research Institute, Otsuka Pharmaceutical, Tokushima, Japan

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  • Published: November 28, 2006
  • DOI: 10.1371/journal.pmed.0030466

About the Authors

Makoto Matsumoto, Hiroyuki Hashizume, Tatsuo Tomishige, Masanori Kawasaki
Microbiological Research Institute, Otsuka Pharmaceutical, Tokushima, Japan
Hidetsugu Tsubouchi, Hirofumi Sasaki, Makoto Komatsu
Medicinal Chemistry Research Institute, Otsuka Pharmaceutical, Tokushima, Japan
Yoshihiko Shimokawa
Tokushima Research Institute, Otsuka Pharmaceutical, Tokushima, Japan

Corresponding Author

Email: m_matsumoto@research.otsuka.co.jp

Competing Interests

All of the authors are working as scientists for Otsuka Pharmaceutical, the originator and owner of OPC-67683 and sole financial supporter of the studies. However, the company is not publicly traded, and none of the authors have or are expected to have stock options.

Author Contributions

All listed authors actively participated in the studies related to OPC-67683 described in this manuscript. M. Matsumoto established a strategy for screening for all synthesized compounds, and was instrumental in selecting and evaluating OPC-67683 through conducting susceptibility tests, establishing the inhibitory activity of OPC-67683 on mycolic acid biosynthesis, and carrying out all in vivo studies involving OPC-67683 in collaboration with H. Hashizume, T. Tomishige, and M. Kawasaki. H. Hashizume was responsible for conducting the bacteria reverse mutation testing and the absorption study in mice. T. Tomishige looked after determining the intracellular activity of OPC-67683 and confirming the potency in the immunosuppressive animal model. M. Kawasaki conducted the studies related to the mechanism of action, susceptibility testing, experimental isolation of resistant strains, confirmation of a mutation in the Rv3547 gene in OPC-67683-resistant strains, and identification of metabolites. H. Tsubouchi and M. Komatsu coordinated the overall activities involved in synthesizing the many novel derivatives for selecting potent antituberculosis agents, and, together with H. Sasaki, synthesized and supplied the derivatives used for in vitro and in vivo evaluations. They also established the facile and practical synthesis method for the intermediates to synthesize many target compounds and supplied derivatives for the screening toxicity test in animals in large scale. H. Sasaki assumed a main role in synthesising various compounds, including OPC-67683. Y. Shimokawa was in charge of the drug interaction studies.