- Improved synthesis of rupintrivir
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An improved synthesis of rupintrivir (AG7088) was accomplished using three amino acids (l-glutamic acid, d-4-fluorophenylalanine, and l-valine) as the building blocks. The key fragment ketomethylene dipeptide isostere was constructed with the valine derivative and phenylpropionic acid derivative, followed by coupling with a lactam derivative and an isoxazole acid chloride to provide AG7088 totally in eight steps.
- Lin, Daizong,Qian, Wangke,Hilgenfeld, Rolf,Jiang, Hualiang,Chen, Kaixian,Liu, Hong
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p. 1101 - 1107
(2012/09/08)
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- Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic α,β-unsaturated esters
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The proteolytic processing of polyproteins by the 3CL protease of severe acute respiratory syndrome coronavirus is essential for the viral propagation. A series of tripeptide α,β-unsaturated esters and ketomethylene isosteres, including AG7088, are synthesized and assayed to target the 3CL protease. Though AG7088 is inactive (IC50 > 100 μM), the ketomethylene isosteres and tripeptide α,β-unsaturated esters containing both P1 and P2 phenylalanine residues show modest inhibitory activity (IC50 = 11-39 μM). The Phe-Phe dipeptide inhibitors 18a-e are designed on the basis of computer modeling of the enzyme-inhibitor complex. The most potent inhibitor 18c with an inhibition constant of 0.52 μM is obtained by condensation of the Phe-Phe dipeptide α,β-unsaturated ester with 4-(dimethylamino)cinnamic acid. The cell-based assays also indicate that 18c is a nontoxic anti-SARS agent with an EC50 value of 0.18 μM.
- Shie, Jiun-Jie,Fang, Jim-Min,Kuo, Tun-Hsun,Kuo, Chih-Jung,Liang, Po-Huang,Huang, Hung-Jyun,Wu, Yin-Ta,Jan, Jia-Tsrong,Cheng, Yih-Shyun E.,Wong, Chi-Huey
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p. 5240 - 5252
(2007/10/03)
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- An efficient and tunable route to AG7088, a rhinovirus protease inhibitor
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Aldol reaction of N,N-dibenzyl valinal with propiolic acid ethyl ester derived lithium reagent provides anti-aminoalcohol 8 and syn-aminoalcohol 9, which are converted into the lactone 6 via two different routes. Alkylation of 6 followed by lactone ring o
- Ma, Dawei,Xie, Weiqing,Zou, Bin,Lei, Qiong,Pei, Duanqing
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p. 8103 - 8105
(2007/10/03)
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- Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics
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The structure-based design, chemical synthesis, and biological evaluation of various ketomethylene-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and an e
- Dragovich, Peter S.,Prins, Thomas J.,Zhou, Ru,Fuhrman, Shella A.,Patick, Amy K.,Matthews, David A.,Ford, Clifford E.,Meador III, James W.,Ferre, Rose Ann,Worland, Stephen T.
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p. 1203 - 1212
(2007/10/03)
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