title: Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors.
abstract: The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an L-Val methyl amide P2 motif by appending hydrogen bonding moieties from either the isopropyl side-chain or from the methyl amide portion. The most promising inhibitors 4a and 4e displayed Ki values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 microM and 0.33 microM respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M46I, V82F, and I84V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone 21 enabling facile modifications of the overall properties in this inhibitor class.
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Adrian Meredith
authors.forename: Hans
authors.initials: H
authors.lastname: Wallberg
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Stefan
authors.initials: S
authors.lastname: Oscarson
authors.forename: Kevin
authors.initials: K
authors.lastname: Parkes
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D015195:Drug Design; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D010539:Permeability; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000438:Alcohols; D017320:HIV Protease Inhibitors; D016333:HIV Protease