Description
PF-06795071 is a potent and selective covalent MAGL inhibitor with MAGL IC50 = 3 nM; FAAH IC50 = 3.1 μM; log D= 3.8; Cb,u/Cp,u = 1.4. PF-06795071 features a novel trifluoromethyl glycol leaving group which confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure; while simultaneously, reducing LogD, improving solubility, and minimizing chemical lability. PF-06795071 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.
