title: ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease.
abstract: The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 microM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, </=0. 06 microM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.
authors.affiliation: Departments of Infectious Diseases Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA. hing.l.sham@abbott.com
authors.forename: H L
authors.initials: HL
authors.lastname: Sham
authors.forename: D J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: A
authors.initials: A
authors.lastname: Molla
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: G N
authors.initials: GN
authors.lastname: Kumar
authors.forename: C M
authors.initials: CM
authors.lastname: Chen
authors.forename: W
authors.initials: W
authors.lastname: Kati
authors.forename: K
authors.initials: K
authors.lastname: Stewart
authors.forename: R
authors.initials: R
authors.lastname: Lal
authors.forename: A
authors.initials: A
authors.lastname: Hsu
authors.forename: D
authors.initials: D
authors.lastname: Betebenner
authors.forename: M
authors.initials: M
authors.lastname: Korneyeva
authors.forename: S
authors.initials: S
authors.lastname: Vasavanonda
authors.forename: E
authors.initials: E
authors.lastname: McDonald
authors.forename: A
authors.initials: A
authors.lastname: Saldivar
authors.forename: N
authors.initials: N
authors.lastname: Wideburg
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Niu
authors.forename: C
authors.initials: C
authors.lastname: Park
authors.forename: V
authors.initials: V
authors.lastname: Jayanti
authors.forename: B
authors.initials: B
authors.lastname: Grabowski
authors.forename: G R
authors.initials: GR
authors.lastname: Granneman
authors.forename: E
authors.initials: E
authors.lastname: Sun
authors.forename: A J
authors.initials: AJ
authors.lastname: Japour
authors.forename: J M
authors.initials: JM
authors.lastname: Leonard
authors.forename: J J
authors.initials: JJ
authors.lastname: Plattner
authors.forename: D W
authors.initials: DW
authors.lastname: Norbeck
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D018360:Crystallography, X-Ray; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D061466:Lopinavir; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011744:Pyrimidinones / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D016333:HIV Protease; D019438:Ritonavir