期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 21, 页码 9346-9361出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3009025
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The evaluation of a series of aminoisoindoles as beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of A beta 40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a so-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC50 values of 8.6 and 0.16 nM, respectively, and hERG IC50 values of 16 and 2.8 mu M, respectively. Several compounds were advanced into pharma codynamic studies and demonstrated significant reduction of beta-amyloid peptides in mouse brain following oral dosing.
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