Molecular Properties Determining Unbound Intracellular and Extracellular Brain Exposure of CNS Drug Candidates
| Autor: | Carola M. Wassvik, Wilhelmus Drinkenburg, Achiel Van Peer, Margareta Hammarlund-Udenaes, Donald Heald, Irena Loryan, An Vermeulen, Claire Mackie, Vikash K. Sinha |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Drug media_common.quotation_subject Central nervous system Pharmaceutical Science Pharmacology Rats Sprague-Dawley Pharmacokinetics Drug Discovery Extracellular medicine Animals Humans Distribution (pharmacology) Pharmaceutical sciences media_common Models Statistical Chemistry Drug discovery Brain Rats medicine.anatomical_structure Blood-Brain Barrier Molecular Medicine Intracellular Central Nervous System Agents |
| Zdroj: | Molecular Pharmaceutics. 12:520-532 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/mp5005965 |
| Popis: | In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the blood-brain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (Kp,uu,brain), intracellular accumulation (Kp,uu,cell), and binding and distribution in the brain (Vu,brain) for a set of 40 compounds were identified using partial least-squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties. |
| Databáze: | OpenAIRE |
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