Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
| Autor: | Johan Unge, Alejandro Trejos, Xiongyu Wu, Mats Larhed, Per Öhrngren, Lotta Vrang, Åsa Rosenquist, Advait Arun Joshi, Magnus Persson, Hans Wallberg, Riina K. Arvela, Bertil Samuelsson |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Cell Membrane Permeability Lactams Stereochemistry medicine.medical_treatment Stereoisomerism Crystallography X-Ray Article chemistry.chemical_compound Structure-Activity Relationship HIV-1 protease HIV Protease Drug Discovery medicine Structure–activity relationship HIV Protease Inhibitor Humans Protease biology Molecular Structure Chemistry Absolute configuration HIV Protease Inhibitors Protease inhibitor (biology) Lactam biology.protein HIV-1 Molecular Medicine Caco-2 Cells medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K(i) of 2.1 nM and an EC(50) of 0.64 μM. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K(i) = 0.8 nM, EC(50) = 0.04 μM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer). |
| Databáze: | OpenAIRE |
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