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Synthesis and antiviral activity of P1' arylsulfonamide azacyclic urea HIV protease inhibitors 总被引:2,自引:0,他引:2
Huang PP Randolph JT Klein LL Vasavanonda S Dekhtyar T Stoll VS Kempf DJ 《Bioorganic & medicinal chemistry letters》2004,14(15):4075-4078
A series of novel azacyclic urea HIV protease inhibitors bearing a benzenesulfonamide group at P1' were synthesized utilizing a parallel synthesis method. Structural studies of early analogs bound in the enzyme active site were used to design more potent inhibitors. The effects of substituting the P1' benzenesulfonyl group on antiviral activity and protein binding are described. 相似文献
2.
Sham HL Zhao C Li L Betebenner DA Saldivar A Vasavanonda S Kempf DJ Plattner JJ Norbeck DW 《Bioorganic & medicinal chemistry letters》2002,12(21):3101-3103
The HIV protease inhibitor Lopinavir has a pseudosymmetric core unit incorporating benzyl groups at both P-1, P-1' positions. A series of analogues incorporating non-aromatic side chains at the P-1 position were synthesized and the structure-activity relationships explored. 相似文献
3.
Zhao C Sham HL Sun M Stoll VS Stewart KD Lin S Mo H Vasavanonda S Saldivar A Park C McDonald EJ Marsh KC Klein LL Kempf DJ Norbeck DW 《Bioorganic & medicinal chemistry letters》2005,15(24):7604-5503
As part of our efforts to identify potent HIV-1 protease inhibitors that are active against resistant viral strains, structural modification of the azacyclic urea (I) was undertaken by incorporating acyl groups as P1′ ligands. The extensive SAR study has yielded a series of N-acyl azacyclic ureas (II), which are highly potent against both wild-type and multiple PI-resistant viral strains. 相似文献
4.
Xiaoqi Chen Dale J. Kempf Hing L. Sham Brian E. Green Akhteruzaman Molla Marina Korneyeva Sudthida Vasavanonda Norman E. Wideburg Ayda Saldivar Kennan C. Marsh Edith McDonald Daniel W. Norbeck 《Bioorganic & medicinal chemistry letters》1998,8(24):6085-3536
The 2-isopropyl thiazolyl group is a highly optimized P3 ligand for C2 symmetry-based HIV protease inhibitors, as exemplified in the drug ritonavir. Here we report that incorporation of this P3 ligand into a piperazine hydroxyethylamine series also yielded novel, highly potent inhibitors. In tissue culture assays, the presence of human serum was less deleterious to the activity of these inhibitors than to that of ritonavir. Furthermore, potent activity against ritonavir resistant HIV was observed. 相似文献
5.
Synthesis and antiviral activities of the major metabolites of the HIV protease inhibitor ABT-378 (Lopinavir) 总被引:1,自引:0,他引:1
Sham HL Betebenner DA Herrin T Kumar G Saldivar A Vasavanonda S Molla A Kempf DJ Plattner JJ Norbeck DW 《Bioorganic & medicinal chemistry letters》2001,11(11):1351-1353
The HIV protease inhibitor ABT-378 (Lopinavir) is metabolized rapidly and extensively by CYP-3A4 catalyzed oxidation. Three of the major metabolites identified were synthesized and their antiviral (HIV) activities determined. 相似文献
6.
Sham HL Betebenner DA Chen X Saldivar A Vasavanonda S Kempf DJ Plattner JJ Norbeck DW 《Bioorganic & medicinal chemistry letters》2002,12(8):1185-1187
The HIV protease inhibitor ABT-378 (Lopinavir) has a 2,6-dimethylphenoxyacetyl group in the P-2' position. Analogues in which this group is replaced with various substituted phenyl or heteroaryl groups were synthesized and the structure-activity relationships explored. 相似文献
7.
Liu Y Jiang WW Pratt J Rockway T Harris K Vasavanonda S Tripathi R Pithawalla R Kati WM 《Biochemistry》2006,45(38):11312-11323
Little is known about the mechanism of HCV polymerase-catalyzed nucleotide incorporation and the individual steps employed by this enzyme during a catalytic cycle. In this paper, we applied various biochemical tools and examined the mechanism of polymerase catalysis. We found that formation of a productive RNA-enzyme complex is the slowest step followed by RNA dissociation and initiation of primer strand synthesis. Various groups have reported several classes of small molecule inhibitors of hepatitis C virus NS5B polymerase; however, the mechanism of inhibition for many of these inhibitors is not clear. We undertook a series of detailed mechanistic studies to characterize the mechanisms of inhibition for these HCV polymerase inhibitors. We found that the diketoacid derivatives competitively bind to the elongation NTP pocket in the active site and inhibit both the initiation and elongation steps of polymerization. While both benzimidazoles and benzothiadiazines are noncompetitive with respect to the active site elongation NTP pocket, benzothiadiazine compounds competitively bind to the initiation pocket in the active site and inhibit only the initiation step of de novo RNA polymerization. The benzimidazoles bind to the thumb allosteric pocket and inhibit the conformational changes during RNA synthesis. We also observed a cross interaction between the thumb allosteric pocket and the initiation pocket using inhibitor-inhibitor cross competition studies. This information will be very important in designing combination therapies using two small molecule drugs to treat hepatitis C virus. 相似文献
8.
Sham HL Betebenner DA Rosenbrook W Herrin T Saldivar A Vasavanonda S Plattner JJ Norbeck DW 《Bioorganic & medicinal chemistry letters》2004,14(10):2643-2645
The HIV protease inhibitor ABT-378 (lopinavir) has a six-member cyclic urea in the P-2 position. A series of analogues in which the six-member cyclic urea is replaced by various heterocycles was synthesized and the structure-activity relationships explored. 相似文献
9.
Synthesis and SAR studies of potent HIV protease inhibitors containing novel dimethylphenoxyl acetates as P2 ligands 总被引:1,自引:0,他引:1
Chen X Kempf DJ Li L Sham HL Vasavanonda S Wideburg NE Saldivar A Marsh KC McDonald E Norbeck DW 《Bioorganic & medicinal chemistry letters》2003,13(21):3657-3660
Isopropyl substituted 4-thioazolyl valine side chains are highly optimized P(2)-P(3) ligands for C2 symmetry-based HIV protease inhibitors, as exemplified by the drug ritonavir. Replacement of the side chain with the conformationally constrained hexahydrofurofuranyloxy P(2) ligand in combination with a dimethylphenoxyacetate on the other end of the ritonavir core diamine yielded highly potent HIV protease inhibitors. The in vitro antiviral activity in MT4 cells increased by 10- and 20-fold, respectively, in the absence and presence of 50% human serum compared to ritonavir. The structure-activity relationships of inhibitor series with this combination of ligands were investigated. Preliminary pharmacokinetic studies in rats indicated rapid elimination of the inhibitors from the blood, and the plasma levels were not significantly enhanced by coadministration with ritonavir. However, the novel structural features and the high intrinsic antiviral potency of this series provides potential for the future exploration of prodrug strategies. 相似文献
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