Tunable Methacrylamides for Covalent Ligand Directed Release Chemistry.

ABSTRACT: Targeted covalent inhibitors are an important class of drugs and chemical probes. However, relatively few electrophiles meet the criteria for successful covalent inhibitor design. Here we describe α-substituted methacrylamides as a new class of electrophiles suitable for targeted covalent inhibitors. While typically α-substitutions inactivate acrylamides, we show that hetero α-substituted methacrylamides have higher thiol reactivity and undergo a conjugated addition-elimination reaction ultimately releasing the substituent. Their reactivity toward thiols is tunable and correlates with the pK_a/pK_b of the leaving group. In the context of the BTK inhibitor ibrutinib, these electrophiles showed lower intrinsic thiol reactivity than the unsubstituted ibrutini

SUBMITTER: Reddi RN 

PROVIDER: S-EPMC8041284 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature