(Carbonyl)oxyalkyl linker-based amino acid prodrugs of the HIV-1 protease inhibitor atazanavir that enhance oral bioavailability and plasma trough concentration
| Autor: | Priyadeep Bhutani, John F. Kadow, Rambabu Arla, Sarmistha Sinha, Murugaiah A. M. Subbaiah, Susan Jenkins, Murali Subramanian, Salil D. Desai, Shweta Padmanabhan, Sandhya Mandlekar, Nicholas A. Meanwell, Lakshumanan Subramani, Srikanth Sridhar, Mark Krystal, Thangeswaran Ramar |
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| Rok vydání: | 2020 |
| Předmět: |
Alkylation
Tertiary amine Atazanavir Sulfate Biological Availability 01 natural sciences 03 medical and health sciences Drug Stability HIV Protease HIV-1 protease Drug Discovery medicine Humans Prodrugs Amines Amino Acids 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences biology 010405 organic chemistry Chemistry Organic Chemistry HIV Protease Inhibitors General Medicine Prodrug Combinatorial chemistry 0104 chemical sciences Bioavailability Atazanavir Amino acid biology.protein Amine gas treating Linker medicine.drug |
| Zdroj: | European Journal of Medicinal Chemistry. 207:112749 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2020.112749 |
| Popis: | We describe the design, synthesis and pharmacokinetic (PK) evaluation of a series of amino acid-based prodrugs of the HIV-1 protease inhibitor atazanavir (1) derivatized on the pharmacophoric secondary alcohol using a (carbonyl)oxyalkyl linker. Prodrugs of 1 incorporating simple (carbonyl)oxyalkyl-based linkers and a primary amine in the promoiety were found to exhibit low chemical stability. However, chemical stability was improved by modifying the primary amine moiety to a tertiary amine, resulting in a 2-fold enhancement of exposure in rats following oral dosing compared to dosing of the parent drug 1. Further refinement of the linker resulted in the discovery of 22 as a prodrug that delivered the parent 1 to rat plasma with a 5-fold higher AUC and 67-fold higher C24 when compared to oral administration of the parent drug. The PK profile of 22 indicated that plasma levels of this prodrug were higher than that of the parent, providing a more sustained release of 1 in vivo. |
| Databáze: | OpenAIRE |
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