Probing Fluorinated Motifs onto Dual AChE-MAO B Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Early-ADME Studies

Rullo Mariagrazia; Cipolloni Marco; Catto MarcoColliva CarolinaMiniero Daniela ValeriaLatronico Tizianade Candia ModestoBenicchi TizianaLinusson AnnaGiacche NicolaAltomare Cosimo DamianoPisani Leonardo

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Probing Fluorinated Motifs onto Dual AChE-MAO B Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Early-ADME Studies

机译：Probing Fluorinated Motifs onto Dual AChE-MAO B Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Early-ADME Studies

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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 (Sol(7.4), CHI7.4, log D-7.4), 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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《Journal of Medicinal Chemistry》 |2022年第5期|3962-3977|共16页
作者
Rullo Mariagrazia; Cipolloni Marco; Catto MarcoColliva CarolinaMiniero Daniela ValeriaLatronico Tizianade Candia ModestoBenicchi TizianaLinusson AnnaGiacche NicolaAltomare Cosimo DamianoPisani Leonardo;
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Univ Bari Aldo Moro;

TES Pharma Srl;

Umea Univ;

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正文语种英语
中图分类药学;
关键词
MONOAMINE-OXIDASE-B; ALZHEIMERS-DISEASE; DIRECTED LIGANDS; SERUM-ALBUMIN; WEB SERVER; ACETYLCHOLINESTERASE; DRUG; CHOLINESTERASE; DERIVATIVES; DISCOVERY;

Probing Fluorinated Motifs onto Dual AChE-MAO B Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Early-ADME Studies

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