期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 19, 页码 14175-14191出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00935
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A novel class of BACE1 inhibitors with optimized structure and properties was developed in this study, achieving target selectivity and efficacy. By addressing potential toxicity issues through compound optimization, a drug candidate with potential clinical value was obtained.
The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid beta lowering without showing BACE2dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future.
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