Discovery of imidazolidine-2,4-dione-linked HIV protease inhibitors with activity against lopinavir-resistant mutant HIV
A new series of HIV protease inhibitors has been designed and synthesized based on the combination of the (R)-(hydroxyethylamino)sulfonamide isostere and the cyclic urea component of lopinavir. The series was optimized by replacing the 6-membered cyclic urea linker with an imidazolidine-2,4-dione which readily underwent N-alkylation to incorporate various methylene-linked heterocycle groups that bind favorably in site 3 of HIV protease. Significant improvements compared to lopinavir were seen in cell culture activity versus wild-type virus (pNL4-3) and the lopinavir-resistant mutant virus A17 (generated by in vitro serial passage of HIV-1 (pNL4-3) in MT-4 cells). Select imidazolidine-2,4-dione containing PIs were also more effective at inhibiting highly resistant patient isolates Pt1 and Pt2 than lopinavir. Pharmacokinetic data collected for compounds in this series varied considerably when coadministered orally in the rat with an equal amount of ritonavir (5 mg/kg each). The AUC values ranged from 0.144 to 12.33 μg h/mL.
Flosi, William J.,DeGoey, David A.,Grampovnik, David J.,Chen, Hui-ju,Klein, Larry L.,Dekhtyar, Tatyana,Masse, Sherie,Marsh, Kennan C.,Mo, Hong Mei,Kempf, Dale
p. 6695 - 6712
(2007/10/03)
Retroviral protease inhibiting compounds
A compound comprising a substituent of the formula (II) is disclosed as an HIV protease inhibitor. Intermediates for making such compounds and processes for making such intermediates are also disclosed.
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Page 57
(2010/01/31)
Synthesis and antiviral activities of the major metabolites of the HIV protease inhibitor ABT-378 (Lopinavir)
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.
Sham, Hing L,Betebenner, David A,Herrin, Thomas,Kumar, Gondi,Saldivar, Ayda,Vasavanonda, Sudthida,Molla, Akhter,Kempf, Dale J,Plattner, Jacob J,Norbeck, Daniel W
p. 1351 - 1353
(2007/10/03)
RETROVIRAL PROTEASE INHIBITING COMPOUNDS
A compound of the formula: STR1 is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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(2008/06/13)
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