Case Study: Fosinopril

Petrillo, Edward W.

doi:10.1007/978-0-387-49785-3_42

Cited by 2 publications

(1 citation statement)

References 11 publications

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“…44 In addition, isobutyraldehyde is a food additive permitted for human consumption as a synthetic flavoring substance and adjuvant by the Federal Drug Administration (FDA). Clinical precedent for the release of isobutyraldehyde as a byproduct of prodrug activation is illustrated by the marketed drug fosinopril, 45 a prodrug of the phosphinic acidbased angiotensin-converting enzyme inhibitor fosinoprilat, and arbaclofen placarbil, 46 a prodrug of the gamma amino butyric acid type B receptor agonist arbaclofen.…”

Section: ■ Introductionmentioning

confidence: 99%

Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir

et al. 2018

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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.

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Section: ■ Introductionmentioning

confidence: 99%

Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir

et al. 2018

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Physicochemical Property Trends of Marketed Prodrugs

Landis

2013

Therapeutic Delivery

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Many prodrug reviews describe specific examples of the successful application of prodrug technology to produce blockbuster drugs, such as simvastatin, omeprazole, acyclovir and enalapril. These reviews are helpful to understand the previous success stories and case histories of prodrug technology. The aim of the current review seeks to more clearly define quantitative trends in the changes in the physicochemical property parameters between the successful prodrug and the active parent molecule. This information can serve to guide medicinal chemists toward more successful pharmaceutical prodrugs in the future.

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Case Study: Fosinopril

Cited by 2 publications

References 11 publications

Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir

Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir

Physicochemical Property Trends of Marketed Prodrugs

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