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 microg h/mL.
Flosi
William J
WJ
Global Pharmaceutical Research and Development, 200 Abbott Park Road 047D AP52 Abbott Park, IL 60064, USA. bill.flosi@abbott.com
DeGoey
David A
DA
Grampovnik
David J
DJ
Chen
Hui-ju
HJ
Klein
Larry L
LL
Dekhtyar
Tatyana
T
Masse
Sherie
S
Marsh
Kennan C
KC
Mo
Hong Mei
HM
Kempf
Dale
D
D018360:Crystallography, X-Ray; D015195:Drug Design; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000821:virology; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D061466:Lopinavir; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D011744:Pyrimidinones / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D048289:Imidazolidines; D011744:Pyrimidinones; C514490:imidazolidine-2,4-dione; D061466:Lopinavir