title: Disubstituted Bis-THF Moieties as New P2 Ligands in Nonpeptidal HIV-1 Protease Inhibitors (II).
abstract: A series of darunavir analogues featuring a substituted bis-THF ring as P2 ligand have been synthesized and evaluated. Very high affinity protease inhibitors (PIs) with an interesting activity on wild-type HIV and a panel of multi-PI resistant HIV-1 mutants containing clinically observed, primary mutations were identified using a cell-based assay. Crystal structure analysis was conducted on a number of PI analogues in complex with HIV-1 protease.
authors.affiliation: †University of Southampton, School of Chemistry, Highfield, Southampton SO17 1BJ, United Kingdom.
authors.forename: Konrad
authors.initials: K
authors.lastname: Hohlfeld
authors.affiliation: ‡Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Jörg Kurt
authors.initials: JK
authors.lastname: Wegner
authors.affiliation: ‡Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Kesteleyn
authors.affiliation: †University of Southampton, School of Chemistry, Highfield, Southampton SO17 1BJ, United Kingdom.
authors.forename: Bruno
authors.initials: B
authors.lastname: Linclau
authors.affiliation: §Lund University, MAX-lab, Ole Römers väg 1, SE-223 63 Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Unge
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D000069454:Darunavir; D024882:Drug Resistance, Viral; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000081:Acetamides; D005663:Furans; D017320:HIV Protease Inhibitors; D008024:Ligands; D013449:Sulfonamides; D000069454:Darunavir