uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors
Show others and affiliations
2010 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, no 1, 160-170 p.Article in journal (Refereed) Published
Abstract [en]

The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an L-Val methyl amide P2 motif by appending hydrogen bonding moieties from either the isopropyl side-chain or from the methyl amide portion. The most promising inhibitors 4a and 4e displayed K-i values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 mu M and 0.33 mu M respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M461, V82F, and 184V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone 21 enabling facile modifications of the overall properties in this inhibitor class.

Place, publisher, year, edition, pages
2010. Vol. 45, no 1, 160-170 p.
Keyword [en]
HIV, HIV-PI, PI, Aspartic protease
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-138037DOI: 10.1016/j.ejmech.2009.09.038ISI: 000274203000021PubMedID: 19926360OAI: oai:DiVA.org:uu-138037DiVA: diva2:378788
Available from: 2010-12-16 Created: 2010-12-16 Last updated: 2010-12-16Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed
By organisation
Department of Medicinal Chemistry
In the same journal
European Journal of Medicinal Chemistry
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 183 hits
ReferencesLink to record
Permanent link

Direct link