Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold
| Autor: | ‖ Per-Olof Markgren, Bertil Samuelsson, Mathias Alterman, U. Nillroth, Anna Mühlman, Björn Classon, and Anders Hallberg, Magnus Björsne, T. Unge, Helena Danielson, Ingemar Kvarnström |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Peptidomimetic
Stereochemistry medicine.drug_class medicine.medical_treatment Adipates Carboxamide Crystallography X-Ray Chemical synthesis Cell Line Mice Structure-Activity Relationship HIV-1 protease HIV Protease Drug Discovery medicine HIV Protease Inhibitor Animals chemistry.chemical_classification Protease biology Chemistry Molecular Mimicry HIV Protease Inhibitors Amino acid Enzyme inhibitor biology.protein HIV-1 Molecular Medicine Peptides |
| Zdroj: | Journal of medicinal chemistry. 41(20) |
| ISSN: | 0022-2623 |
| Popis: | A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has been undertaken. l-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available materials. A remarkable increase in potency going from IC50 = 5000 nM (23) to IC50 = 15 nM (28) was observed upon exchanging −COOMe for −CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two −NH− groups and the HIV protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined (Figures 5 and 6), revealing the binding mode of these inhibitors which will aid further design. |
| Databáze: | OpenAIRE |
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