| Structural highlights
Publication Abstract from PubMed
A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1' pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1' ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 protease complexes revealed molecular insight into the inhibitor-protein interaction.
Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation.,Ghosh AK, Osswald HL, Glauninger K, Agniswamy J, Wang YF, Hayashi H, Aoki M, Weber IT, Mitsuya H J Med Chem. 2016 Jul 28;59(14):6826-37. doi: 10.1021/acs.jmedchem.6b00639. Epub, 2016 Jul 7. PMID:27389367[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ghosh AK, Osswald HL, Glauninger K, Agniswamy J, Wang YF, Hayashi H, Aoki M, Weber IT, Mitsuya H. Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation. J Med Chem. 2016 Jul 28;59(14):6826-37. doi: 10.1021/acs.jmedchem.6b00639. Epub, 2016 Jul 7. PMID:27389367 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00639
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