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Discovery of potent and orally active 1,4-disubstituted indazoles as novel allosteric glucokinase activators |
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| Authors: | Zacharia S Cheruvallath Stephen L Gwaltney Mark Sabat Mingnam Tang Haixia Wang Andy Jennings David Hosfield Bumsup Lee Yiqin Wu Petro Halkowycz Charles E Grimshaw |
| Institution: | 1. Takeda California, 10410 Science Center Drive, San Diego 92121, USA;2. Chrysalis Therapeutics, San Diego, CA 92121, USA;3. Ben May Cancer Institute, University of Chicago, USA;4. Kolon Life Science, Inc, 7FL Kolon Tower Annex, 38 Byeoryangsangga 2-Ro, Gwacheon-Si, Gyeonggi-Do 427-709, Republic of Korea;5. Quanticel Pharmaceuticals Inc., 9393 Towne Centre Drive, Suite 110, San Diego, CA 92121, USA |
| Abstract: | Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes. |
| Keywords: | Glucokinase activator Structure-based drug design OGTT Type 2 diabetes 1 4-Disubstituted indazole |
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