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Epsilon substituted lysinol derivatives as HIV-1 protease inhibitors |
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| Authors: | Kristen LG Jones M Katharine Holloway Hua-Poo Su Steven S Carroll Christine Burlein Sinoeun Touch Daniel J DiStefano Rosa I Sanchez Theresa M Williams Joseph P Vacca Craig A Coburn |
| Institution: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA;2. Department of Molecular Systems, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA;3. Department of Structural Biology, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA;4. Department of Antiviral Research, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA;5. Department of Vaccine Basic Research, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA;6. Department of Drug Metabolism, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA |
| Abstract: | A series of HIV-1 protease inhibitors containing an epsilon substituted lysinol backbone was synthesized. Two novel synthetic routes using N-boc-l-glutamic acid alpha-benzyl ester and 2,6-diaminopimelic acid were developed. Incorporation of this epsilon substituent enabled access to the S2 pocket of the enzyme, affording high potency inhibitors. Modeling studies and synthetic efforts suggest the potency increase is due to both conformational bias and van der Waals interactions with the S2 pocket. |
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