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Microwave-Accelerated Synthesis of P1´-Extended HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol in the Transition-State Mimicking Scaffold
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2006 (English)In: Jounal of Medicinal Chemistry, ISSN 0022-2623, Vol. 49, no 5, 1828-1832 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 49, no 5, 1828-1832 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94227OAI: oai:DiVA.org:uu-94227DiVA: diva2:168008
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2013-07-04Bibliographically approved
In thesis
1. Design and Synthesis of Novel HIV-1 Protease Inhibitors Comprising a Tertiary Alcohol in the Transition-State Mimic
Open this publication in new window or tab >>Design and Synthesis of Novel HIV-1 Protease Inhibitors Comprising a Tertiary Alcohol in the Transition-State Mimic
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

HIV-1 protease inhibitors are important in the most frequently used regimen for the treatment of HIV/AIDS, the highly active antiretroviral therapy (HAART). For patients with access to this treatment, an HIV infection is no longer lethal, but rather a manageable, chronic infection. However, the HIV-1 protease inhibitors are generally associated with serious shortcomings such as adverse events, development of drug resistance and poor pharmacokinetic properties. Most of the approved inhibitors suffer from high protein binding, rapid metabolism and/or low membrane permeability.

In this project, novel HIV-1 protease inhibitors comprising a rarely used tertiary alcohol in the transition-state mimic were designed, synthesized and evaluated. The rationale behind the design was to achieve ‘masking’ of the tertiary alcohol by for example, intramolecular hydrogen bonding, which was believed could enhance transcellular transport.

A reliable synthetic protocol was developed and a series of highly potent inhibitors was obtained exhibiting excellent membrane permeation properties in a Caco-2 cell assay. However, the cellular antiviral potencies of these compounds were low. In an attempt to improve the anti-HIV activity, microwave-accelerated, palladium-catalyzed cross-coupling reactions and aminocarbonylation of aryl bromide precursors were employed to produce P1'-extended test compounds. Inhibitors demonstrating up to six times higher antiviral effect were obtained, the best derivatives having para 3- or 4-pyridyl elongations in P1'.

Fast metabolic degradation was observed in liver microsome homogenate, which is believed, at least partly, to be attributable to benzylic oxidation of the indanol P2 group of the inhibitors. To enable facile variation of the P2 side chain a new synthetic route was developed using an enantiomerically pure, benzyl-substituted epoxy carboxylic acid as the key intermediate. Cyclic and amino-acid-residue-derived P2 groups were evaluated, and inhibitors equipotent to the series containing an indanol moiety were produced.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 72 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 30
Chemistry, HIV/AIDS, HIV-1 protease inhibitor, transition-state mimic, tertiary alcohol, palladium, cross-coupling, aminocarbonylation, microwave, molybdenum hexacarbonyl, Kemi
urn:nbn:se:uu:diva-6737 (URN)91-554-6512-9 (ISBN)
Public defence
2006-04-28, B42, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved

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