化学
广告
亲脂性
CYP3A4型
药理学
IC50型
生物利用度
立体化学
微粒体
阿切
体外
乙酰胆碱酯酶
生物化学
细胞色素P450
酶
医学
作者
Mariagrazia Rullo,Marco Cipolloni,Marco Catto,Carolina Colliva,Daniela Valeria Miniero,Tiziana Latronico,Modesto de Candia,Tiziana Benicchi,Anna Linusson,Nicola Giacchè,Cosimo Altomare,Leonardo Pisani
标识
DOI:10.1021/acs.jmedchem.1c01784
摘要
Bioisosteric H/F or CH2OH/CF2H replacement was introduced in coumarin derivatives previously characterized as dual AChE-MAO B inhibitors to probe the effects on both inhibitory potency and drug-likeness. Along with in vitro screening, we investigated early-ADME parameters related to solubility and lipophilicity (Sol7.4, CHI7.4, log D7.4), oral bioavailability and central nervous system (CNS) penetration (PAMPA-HDM and PAMPA-blood-brain barrier (BBB) assays, Caco-2 bidirectional transport study), and metabolic liability (half-lives and clearance in microsomes, inhibition of CYP3A4). Both specific and nonspecific tissue toxicities were determined in SH-SY5Y and HepG2 lines, respectively. Compound 15 bearing a -CF2H motif emerged as a water-soluble, orally bioavailable CNS-permeant potent inhibitor of both human AChE (IC50 = 550 nM) and MAO B (IC50 = 8.2 nM, B/A selectivity > 1200). Moreover, 15 behaved as a safe and metabolically stable neuroprotective agent, devoid of cytochrome liability.
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