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Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors.

Abstract：

: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 Ki values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 microM and 0.33 microM 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 M46I, V82F, and I84V 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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Adrian Meredith J,Wallberg H,Vrang L,Oscarson S,Parkes K,Hallberg A,Samuelsson B

doi

10.1016/j.ejmech.2009.09.038

subject

Has Abstract

pub_date

2010-01-01 00:00:00

pages

160-70

issue

1

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(09)00489-9

journal_volume

45

pub_type

杂志文章

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