Pyrazole inhibitors of HMG-CoA reductase: An attempt to dramatically reduce synthetic complexity through minimal analog re-design

An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker (‘oxypyrazoles’). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity.

A highly effective new series of pyrazole statins 3 was transformed by a single atom change to the oxypyrazoles 4, reducing a complex synthetic route from 14 to 7 steps. Although the new analogs retained most of the in vitro activity of the pyrazoles, they had inferior in vivo activity.Figure optionsDownload as PowerPoint slide