2 research outputs found
Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA<sub>2</sub> Inhibitor
We describe the incorporation
of a bicyclo[1.1.1]pentane moiety
within two known LpPLA<sub>2</sub> inhibitors to act as bioisosteric
phenyl replacements. An efficient synthesis to the target compounds
was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane
system being the key transformation. Potency, physicochemical, and
X-ray crystallographic data were obtained to compare the known inhibitors
to their bioisosteric counterparts, which showed the isostere was
well tolerated and positively impacted on the physicochemical profile
Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA<sub>2</sub>)
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