1 research outputs found

    Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA<sub>2</sub>)

    No full text
    Lp-PLA<sub>2</sub> has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA<sub>2</sub>. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC<sub>50</sub> > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA<sub>2</sub> inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile
    corecore