Structure-based characterization and optimization of novel hydrophobic binding interactions in a series of pyrrolidine influenza neuraminidase inhibitors.
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| Abstract |
The structure-activity relationship (SAR) of a novel hydrophobic binding interaction within a subsite of the influenza neuraminidase (NA) active site was characterized and optimized for a series of trisubstituted pyrrolidine inhibitors modified at the 4-position. Previously, potent inhibitors have targeted this subsite with hydrophilic substituents such as amines and guanidines. Inhibitor-bound crystal structures revealed that hydrophobic substituents with sp(2) hybridization could achieve optimal interactions by virtue of a low-energy binding conformation and favorable pi-stacking interactions with the residue Glu119. From a lead methyl ester, investigation of five-membered heteroaromatic substituents at C-4 produced a 3-pyrazolyl analogue that improved activity by making a targeted hydrogen bond with Trp178. The SAR of substituted vinyl substituents at C-4 produced a Z-propenyl analogue with improved activity over the lead methyl ester. The C-1 ethyl ester prodrugs of the substituted C-4 vinyl analogues gave compounds with excellent oral bioavailability (F > 60%) when dosed in rat.
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| Authors | Clarence J Maring, Vincent S Stoll, Chen Zhao, Minghua Sun, Allan C Krueger, Kent D Stewart, Darold L Madigan, Warren M Kati, Yibo Xu, Robert J Carrick, Debra A Montgomery, Anita Kempf-Grote, Kennan C Marsh, Akhteruzzaman Molla, Kevin R Steffy, Hing L Sham, W Graeme Laver, Yu-gui Gu, Dale J Kempf, William E Kohlbrenner |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 12 Pg. 3980-90 (Jun 16 2005) ISSN: 0022-2623 [Print] United States |
| PMID | 15943472 (Publication Type: Journal Article) |
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