Structure–Activity Relationships of Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors: Investigations of Various 6,5-Heterocycles to Improve Metabolic Stability

Abstract

N-(6-(6-Chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (1) is a potent and efficacious inhibitor of PI3Kα and mTOR in vitro and in vivo. However, in hepatocyte and in vivo metabolism studies, 1 was found to undergo deacetylation on the 2-amino substituent of the benzothiazole. As an approach to reduce or eliminate this metabolic deacetylation, a variety of 6,5-heterocyclic analogues were examined as an alternative to the benzothiazole ring. Imidazopyridazine 10 was found to have similar in vitro potency and in vivo efficacy relative to 1, while only minimal amounts of the corresponding deacetylated metabolite of 10 were observed in hepatocytes.