title: DPC 681 and DPC 684: potent, selective inhibitors of human immunodeficiency virus protease active against clinically relevant mutant variants.
abstract: Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC(90)). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC(90)s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC(50) values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC(50) values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir).
authors.affiliation: Department of Chemistry and Physical Sciences, DuPont Pharmaceuticals Co., Wilmington, Delaware 19880-0336, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Kaltenbach
authors.forename: G
authors.initials: G
authors.lastname: Trainor
authors.forename: D
authors.initials: D
authors.lastname: Getman
authors.forename: G
authors.initials: G
authors.lastname: Harris
authors.forename: S
authors.initials: S
authors.lastname: Garber
authors.forename: B
authors.initials: B
authors.lastname: Cordova
authors.forename: L
authors.initials: L
authors.lastname: Bacheler
authors.forename: S
authors.initials: S
authors.lastname: Jeffrey
authors.forename: K
authors.initials: K
authors.lastname: Logue
authors.forename: P
authors.initials: P
authors.lastname: Cawood
authors.forename: R
authors.initials: R
authors.lastname: Klabe
authors.forename: S
authors.initials: S
authors.lastname: Diamond
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.forename: J
authors.initials: J
authors.lastname: Saye
authors.forename: J
authors.initials: J
authors.lastname: Jona
authors.forename: S
authors.initials: S
authors.lastname: Erickson-Viitanen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004352:Drug Resistance, Microbial; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D011485:Protein Binding; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001798:Blood Proteins; C444448:DPC 681; C444449:DPC 684; D017320:HIV Protease Inhibitors; D013449:Sulfonamides