title: Discovery of imidazolidine-2,4-dione-linked HIV protease inhibitors with activity against lopinavir-resistant mutant HIV.
abstract: 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.
authors.affiliation: Global Pharmaceutical Research and Development, 200 Abbott Park Road 047D AP52 Abbott Park, IL 60064, USA. bill.flosi@abbott.com
authors.forename: William J
authors.initials: WJ
authors.lastname: Flosi
authors.forename: David A
authors.initials: DA
authors.lastname: DeGoey
authors.forename: David J
authors.initials: DJ
authors.lastname: Grampovnik
authors.forename: Hui-ju
authors.initials: HJ
authors.lastname: Chen
authors.forename: Larry L
authors.initials: LL
authors.lastname: Klein
authors.forename: Tatyana
authors.initials: T
authors.lastname: Dekhtyar
authors.forename: Sherie
authors.initials: S
authors.lastname: Masse
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Hong Mei
authors.initials: HM
authors.lastname: Mo
authors.forename: Dale
authors.initials: D
authors.lastname: Kempf
mesh_terms: 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
chemical_list: D017320:HIV Protease Inhibitors; D048289:Imidazolidines; D011744:Pyrimidinones; C514490:imidazolidine-2,4-dione; D061466:Lopinavir