Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design

A series of 3,4-disubstituted piperidine
derivatives were obtained
based on a conformational restriction strategy and a lead compound, A12, that exhibited potent in vitro and in vivo antitumor
efficacies; however, obvious safety issues limited its further development.
Thus, systematic exploration of the structure–activity relationship
of compound A12, involving the phenyl group, hinge-linkage,
and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted
piperidine derivative E22. E22 showed increased
potency in Akt1 and cancer cell inhibition, remarkably reduced human
ether-a-go-go-related gene blockage, and significantly improved safety
profiles. Compound E22 also exhibited good kinase selectivity,
had a good pharmacokinetic profile, and displayed very potent in vivo
antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3
xenograft model. Further mechanistic studies were conducted to demonstrate
that compound E22 could significantly inhibit the phosphorylation
of proteins downstream of Akt kinase in cells and tumor tissue from
the xenograft model.