ABSTRACT
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.
Subject(s)
Amino Acids/chemistry , Atazanavir Sulfate/pharmacology , Atazanavir Sulfate/pharmacokinetics , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/pharmacokinetics , HIV Protease/metabolism , Prodrugs/chemistry , Alkylation , Amines/chemistry , Amino Acids/metabolism , Atazanavir Sulfate/blood , Atazanavir Sulfate/metabolism , Biological Availability , Drug Stability , HIV Protease Inhibitors/blood , HIV Protease Inhibitors/metabolism , Humans , Prodrugs/metabolismABSTRACT
Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. Val amino acid and Val-Val dipeptides imparted low plasma exposure of the parent, although the exposure of the prodrugs was high, reflecting good absorption. Screening of additional amino acids resulted in the identification of an l-Phe ester that offered an improved exposure of 1 and reduced levels of the circulating prodrug. Further molecular editing focusing on the linker design culminated in the discovery of the self-immolative l-Phe-Sar dipeptide derivative 74 that gave four-fold improved AUC and eight-fold higher Ctrough values of 1 compared with oral administration of the drug itself, demonstrating a successful prodrug approach to the oral delivery of 1.
Subject(s)
Amino Acids/chemistry , Atazanavir Sulfate/chemistry , Atazanavir Sulfate/pharmacokinetics , Drug Design , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacokinetics , Phosphates/chemistry , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Atazanavir Sulfate/administration & dosage , Atazanavir Sulfate/chemical synthesis , Biological Availability , Esters , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/chemical synthesis , Humans , Prodrugs/administration & dosage , Prodrugs/chemical synthesisABSTRACT
Aims To establish what work a sample of Overseas Registration Examination (ORE) registrants were undertaking and understand what had facilitated or impeded them from finding suitable employment as dentists. Method An online questionnaire, consisting of both closed and open questions, was used to capture data from a population of 1,106 former ORE candidates who passed the examination between 2009 and 2014 and were registered by the General Dental Council (GDC). The data were analysed and presented in the form of tables, figures and a presentation of the major themes that emerged from the responses. Results There was a 42% response rate. Seventy-one percent of respondents were employed as dentists in the UK, with the majority providing a mixture of private and NHS patient treatment. Most who were not working as dentists were actively seeking training places. Additional themes that were identified included: the availability of Dental Foundation/Vocational Training places; poor employment practices; perceptions of the strengths and weaknesses of the ORE; and some ideas about the future responsibilities of the GDC. Conclusions This survey has highlighted some difficulties that many ORE registrants face finding suitable work as dentists. Stakeholders should be aware of these challenges.
Subject(s)
Attitude of Health Personnel , Dentists , Employment , Humans , Surveys and QuestionnairesABSTRACT
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.
