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Probing Fluorinated...
Probing Fluorinated Motifs onto Dual AChE-MAO B Inhibitors : Rational Design, Synthesis, Biological Evaluation, and Early-ADME Studies
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- Rullo, Mariagrazia (author)
- Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy
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- Cipolloni, Marco (author)
- TES Pharma s.r.l., Corso Vannucci 47, Perugia, Italy
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- Catto, Marco (author)
- Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy
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- Colliva, Carolina (author)
- TES Pharma s.r.l., Corso Vannucci 47, Perugia, Italy
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- Miniero, Daniela Valeria (author)
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", via Orabona, 4, Bari, Italy
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- Latronico, Tiziana (author)
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", via Orabona, 4, Bari, Italy
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- De Candia, Modesto (author)
- Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy
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- Benicchi, Tiziana (author)
- TES Pharma s.r.l., Corso Vannucci 47, Perugia, Italy
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- Linusson, Anna, 1970- (author)
- Umeå universitet,Kemiska institutionen
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- Giacchè, Nicola (author)
- TES Pharma s.r.l., Corso Vannucci 47, Perugia, Italy
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- Altomare, Cosimo Damiano (author)
- Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy
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- Pisani, Leonardo (author)
- Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy
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Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy TES Pharma sr.l., Corso Vannucci 47, Perugia, Italy (creator_code:org_t)
- 2022-02-23
- 2022
- English.
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:5, s. 3962-3977
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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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 (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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
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Rullo, Mariagraz ...
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Cipolloni, Marco
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Catto, Marco
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Colliva, Carolin ...
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Miniero, Daniela ...
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Latronico, Tizia ...
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De Candia, Modes ...
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Benicchi, Tizian ...
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Linusson, Anna, ...
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Giacchè, Nicola
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Altomare, Cosimo ...
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Pisani, Leonardo
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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Umeå University