- Enzyme assisted syntheses of chiral building blocks for isosters of diglycerides, phospholipids and PAF
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Lipase catalyzed desymmetrizations of suitably substituted, achiral 1,3-diols lead to the corresponding chiral building blocks of high enantiomeric purities, starting materials for the synthesis of isosteric carba-analogues of 1,2-sn-diglycerides and phospholipids with interesting biological activities. Lipase catalyzed resolutions of the corresponding ether derivatives lead to the corresponding building blocks for carba-analogues of PAF.
- Lange, Karsten,Schneider, Manfred P.
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p. 2811 - 2815
(2007/10/03)
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- Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design
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A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, his tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein- ligand complex of 9 revealed the inhibitor binds in an inverted binding mode relative to 3. Examination of the protein-ligand complex of 9 suggested several modifications in the P1 and P1' pockets. Through these modifications it was possible to improve the activity of the inhibitors another 100-fold, highlighting the utility of crystallographic feedback in inhibitor design. These compounds were found to have good antiviral activity in cell culture, were selective for the HIV protease, and were orally available in three animal models.
- Melnick, Michael,Reich, Siegfried H.,Lewis, Kathy K.,Mitchell Jr., Lennert J.,Nguyen, Dzuy,Trippe, Anthony J.,Dawson, Heather,Davies II, Jay F.,Appelt, Krzysztof,Wu, Bor-Wen,Musick, Linda,Gehlhaar, Dan K.,Webber, Stephanie,Shetty, Bhasker,Kosa, Maha,Kahil, Deborah,Andrada, Dominic
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p. 2795 - 2811
(2007/10/03)
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