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Variations of the P2 Group in HIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Transition-State Mimicking Scaffold
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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2006 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, no 16, 3040-3043 p.Article in journal (Refereed) Published
Abstract [en]

The development of synthetic protocol leading to HIV-1 protease inhibitors with a tertiary alcohol based transition-state mimicking unit and different P2 side chains was investigated. (2S)-2-benztloxirane-2-carboxylic acid ((S)-5) was used as a key intermediate in the synthesis of the new HIV-1 protease inhibitors. (S)-5 was coupled with different amines using EDC, NMM, and HOBT, resulting in the corresponding amides at low to moderate yields. The observation supports the hypothesis that intramolecular hydrogen bonding to the tertiary alcohol in the transition-state mimic is present in these molecules. Purification by reverse-phase LC-MS resulted in moderate to good yields of most target compounds. The HIV-1 protease inhibition data suggest that the size and polarity of the P2 substituent are crucial to allow proper accommodation in the S2 sub-site.

Place, publisher, year, edition, pages
2006. Vol. 4, no 16, 3040-3043 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94229DOI: 10.1039/b606859fISI: 000239508100003PubMedID: 16886068OAI: oai:DiVA.org:uu-94229DiVA: diva2:168010
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 30
Keyword
Chemistry, HIV/AIDS, HIV-1 protease inhibitor, transition-state mimic, tertiary alcohol, palladium, cross-coupling, aminocarbonylation, microwave, molybdenum hexacarbonyl, Kemi
Identifiers
urn:nbn:se:uu:diva-6737 (URN)91-554-6512-9 (ISBN)
Public defence
2006-04-28, B42, BMC, Husargatan 3, Uppsala, 09:15
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Supervisors
Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved

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Gising, JohanLarhed, MatsHallberg, Anders

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