Design, Synthesis and Biological Evaluation of 4‐Aminopyrimidine or 4,6‐Diaminopyrimidine Derivatives as Beta Amyloid Cleaving Enzyme‐1 (BACE1) Inhibitors

A series of novel aminopyrimidine and diaminopyrimidine derivatives were designed and optimized to improve their potency and bloodbrain‐barrier (BBB) permeability relative to lead compound 1 (IC50 = 37.4 ± 1.2 μM). The optimized compound 13g was 26‐fold more potent than compound 1 based on FRET assay, and PAMPA result suggested that it could pass through the BBB.

Abstract

A series of novel aminopyrimidine and diaminopyrimidine derivatives were designed and optimized to improve their potency and permeability relative to lead compound 1 (IC₅₀ = 37.4 μM), which was discovered in a previous virtual screening. The potency of the optimized compound, 13g (IC₅₀ = 1.4 μM), was 26‐fold greater than that of 1 based on a fluorescence resonance energy transfer (FRET) assay, and a parallel artificial membrane permeability assay (PAMPA) suggested that it could pass through the blood‐brain barrier (BBB). Additionally, several compounds containing selenium showed good potencies and deserve further investigation as anti‐Alzheimer's agents.

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