In Retrospect: Root-Cause Analysis of Structure-Activity Relationships in IRAK4 Inhibitor Zimlovisertib (PF-06650833)
Within this paper, we disclose insights around the root reasons for three structure-activity relationship (SAR) observations experienced within the discovery from the IRAK4 inhibitor Zimlovisertib (PF-06650833). The very first is a nonlinear potency SAR experienced using the isoquinoline ether substituent, the second reason is a potency enhancement created by fluorine substitution around the lactam, and also the third is really a slight potency preference for those-syn (2S,3S,4S) stereochemistry within the fluorine-substituted lactam. We present new data which help to tell us from the origins of those unpredicted SAR trends.