Discovery of novel 7-membered cyclic amide derivatives that inhibit 11beta-hydroxysteroid dehydrogenase type 1 |
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Authors: | Shuji Udagawa Satoshi Sakami Takahiro Takemura Mikiya Sato Takahiro Arai Aiko Nitta Takumi Aoki Koji Kawai Tomokatsu Iwamura Seiji Okazaki Takehiro Takahashi Mie Kaino |
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Institution: | Toray Industries, Inc., Pharmaceutical Research Laboratories, 10-1 Tebiro 6-chome, Kamakura, Kanagawa 248-8555, Japan |
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Abstract: | A series of novel 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo4,3-c]azepin-4(1H)-ones that inhibit 11beta-hydroxysteroid dehydrogenase type 1 are described. We discovered these 7-membered cyclic amide derivatives by introducing a distinctive linker through pharmacophore analysis of known ligands included in X-ray co-crystal structures. Further optimization using docking studies led to highly potent inhibitors 15b and 27, which furthermore showed the potent efficacy in in vivo studies. |
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