1-((S)-gamma-substituted prolyl)-(S)-2-cyanopyrrolidine as a novel series of highly potent DPP-IV inhibitors |
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Authors: | Sakashita Hiroshi Kitajima Hiroshi Nakamura Mitsuharu Akahoshi Fumihiko Hayashi Yoshiharu |
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Affiliation: | Pharmaceuticals Research Unit, Research & Development Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. |
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Abstract: | 1-(Gamma-substituted prolyl)-(S)-2-cyanopyrrolidines were designed based on the predicted binding mode of the known DPP-IV inhibitor NVP-DPP728 and evaluated for their inhibitory activity. In structure-activity relationship study at the gamma-position of proline, it became clear that compounds bearing (S)-stereochemistry were 20-fold more potent than the antipode. Of these compounds, the (3,4-dicyanophenyl)amino- and (3-chloro-4-cyanophenyl)amino-derivatives showed the highest inhibitory activity. |
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