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Conformation and Atropisomeric Properties of Indometacin Derivatives |
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| Authors: | Shintaro Wakamatsu Yuka Takahashi Dr. Hidetsugu Tabata Dr. Tetsuta Oshitari Norihiko Tani Prof. Dr. Isao Azumaya Dr. Yukiteru Katsumoto Dr. Takeyuki Tanaka Dr. Shinzo Hosoi Prof. Dr. Hideaki Natsugari Prof. Dr. Hideyo Takahashi |
| Affiliation: | 1. School of Pharmaceutical Sciences, Teikyo University, 2‐11‐1 Kaga, Itabashi‐ku, Tokyo 173‐8605 (Japan);2. Faculty of Pharmaceutical Sciences, Kagawa Campus, Tokushima Bunri University, 1314‐1 Shido, Sanuki, Kagawa 769‐2193 (Japan);3. Department of Chemistry, Graduate School of Science, Hiroshima University, Higashi‐Hiroshima, Hiroshima 739‐8256 (Japan);4. Integrated Center of Science, Ehime University, 3‐5‐7 Tarumi, Matsuyama, Ehime 790‐8566 (Japan);5. Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, 1 Shichono‐cho, Misasagi, Yamashina‐ku, Kyoto 607‐8412, (Japan) |
| Abstract: | The stereochemistry around the N‐benzoylated indole moiety of indometacin was studied by restricting the rotation about the N? C7′ and/or C7′? C1′ bond. In the 2′,6′‐disubstituted ones, an atropisomeric property was found and the atropoisomers were separated and isolated as stable forms. Their biological abilities to inhibit cyclooxygenase‐1 (COX‐1) and cyclooxygenase‐2 (COX‐2) were examined. Only the aR‐isomer showed specific inhibition of COX‐1, and COX‐2 was not inhibited by either atropisomer. Conformational analysis in NMR studies and X‐ray crystallography, and CD spectra in combination with calculations were utilized to elucidate the bioactive conformations. |
| Keywords: | chirality conformational analysis drug design nitrogen heterocycles stereochemistry |