Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir
| Autor: | Mathiazhagan Annadurai, Ramakanth Sarabu, Salil D. Desai, John F. Kadow, Nicholas A. Meanwell, Sarmistha Sinha, Susan Jenkins, Murali Subramanian, Rambabu Arla, Murugaiah A. M. Subbaiah, Thangeswaran Ramar, Shweta Padmanabhan, Priyadeep Bhutani, Mark Krystal, Chunfu Wang, Sandhya Mandlekar, Lakshumanan Subramani, Srikanth Sridhar |
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| Rok vydání: | 2018 |
| Předmět: |
Drug
medicine.medical_treatment media_common.quotation_subject Atazanavir Sulfate Administration Oral Biological Availability Pharmacology 030226 pharmacology & pharmacy Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Pharmacokinetics HIV-1 protease In vivo Drug Discovery medicine Animals Prodrugs Tissue Distribution media_common Protease biology Symporters Chemistry HIV Protease Inhibitors Prodrug Fatty Acid Transport Proteins Atazanavir Bioavailability Rats 030220 oncology & carcinogenesis biology.protein Molecular Medicine medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 61(9) |
| ISSN: | 1520-4804 |
| Popis: | HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, 1), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug-drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of 1 but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of 1 when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with 1, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs. |
| Databáze: | OpenAIRE |
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