title: Synthesis and SAR studies of potent HIV protease inhibitors containing novel dimethylphenoxyl acetates as P2 ligands.
abstract: Isopropyl substituted 4-thioazolyl valine side chains are highly optimized P(2)-P(3) ligands for C2 symmetry-based HIV protease inhibitors, as exemplified by the drug ritonavir. Replacement of the side chain with the conformationally constrained hexahydrofurofuranyloxy P(2) ligand in combination with a dimethylphenoxyacetate on the other end of the ritonavir core diamine yielded highly potent HIV protease inhibitors. The in vitro antiviral activity in MT4 cells increased by 10- and 20-fold, respectively, in the absence and presence of 50% human serum compared to ritonavir. The structure-activity relationships of inhibitor series with this combination of ligands were investigated. Preliminary pharmacokinetic studies in rats indicated rapid elimination of the inhibitors from the blood, and the plasma levels were not significantly enhanced by coadministration with ritonavir. However, the novel structural features and the high intrinsic antiviral potency of this series provides potential for the future exploration of prodrug strategies.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, D-47D, AP52, 100 Abbott Park Road, Abbott Park, IL 60064, USA. xchen@tularik.com
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Chen
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Sudthida
authors.initials: S
authors.lastname: Vasavanonda
authors.forename: Norman E
authors.initials: NE
authors.lastname: Wideburg
authors.forename: Ayda
authors.initials: A
authors.lastname: Saldivar
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Edith
authors.initials: E
authors.lastname: McDonald
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Norbeck
mesh_terms: D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D010642:Phenoxyacetates / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D019438:Ritonavir / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D010642:Phenoxyacetates; D019438:Ritonavir