Needless to say, balancing potency gains by adding lipophilicity without introducing metabolic or other liabilities is a general
challenge. We believe the present case study offers an interesting example of productive use of the infrequently utilized
pentafluoroethyl fragment, which is in the rare position of having moderate size and lipophilicity while being resistant to oxidative
2
5,26
metabolism. Contemporary synthetic methods have made incorporation of this group more easily accessible by cross-coupling,
and
many more pentafluoroethylated building blocks are now commercially available. In summary, we discovered a series of RIPK1
inhibitors that derive potency from small lipophilic alkyl groups occupying the protein back pocket, which is normally exploited by
aromatic substituents in published inhibitors. Through judicious use of the pentafluoroethyl motif, we were able to find a compound
with good potency and pharmacokinetic properties.
Acknowledgments
We gratefully acknowledge support from the Genentech Discovery Chemistry Analytical and Purifications, Compound
Management, and Protein Chemistry groups.
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