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Identification and design of a novel series of MGAT2 inhibitors |
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| Authors: | Jonas G Barlind Linda K Buckett Sharon G Crosby Öjvind Davidsson Hans Emtenäs Anne Ertan Ulrik Jurva Malin Lemurell Pablo Morentin Gutierrez Karolina Nilsson Gavin O’Mahony Annika U Petersson Alma Redzic Fredrik Wågberg Zhong-Qing Yuan |
| Institution: | 1. AstraZeneca R&D, Cardiovascular & Gastrointestinal Innovative Medicines Unit Mölndal, SE-431 83 Mölndal, Sweden;2. AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK;3. Dept. of Materials and Environmental Chemistry, Stockholm University, Arrhenius Laboratory, Svante Arrheniusväg 16C, SE-106 91 Stockholm, Sweden |
| Abstract: | Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to na?ve, p <0.01) in plasma triacylglycerol (TAG) concentration. |
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