title: 2',6'-Dimethylphenoxyacetyl: a new achiral high affinity P(3)-P(2) ligand for peptidomimetic-based HIV protease inhibitors.
abstract: Starting from palinavir (1), our lead HIV protease inhibitor, we have discovered a new series of truncated analogues in which the P(3)-P(2) quinaldic-valine portion of 1 was replaced by 2', 6'-dimethylphenoxyacetyl. With EC(50)'s in the 1-2 nM range, some of these compounds are among the most potent inhibitors of HIV replication in vitro, reported to date. One of the most promising members in this series (compound 27, BILA 2185 BS) exhibited a favorable overall pharmacokinetic profile, with 61% apparent oral bioavailability in rat. X-ray crystal structures and molecular modeling were used to rationalize the high potency resulting from incorporation of this structurally simple, achiral ligand into the P(3)-P(2) position of hydroxyethylamine-based HIV protease inhibitors.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., 175 Briar Ridge Road, Ridgefield, Connecticut 06877, USA. pbeaulieu@lav.boehringer-ingelheim.com
authors.forename: P L
authors.initials: PL
authors.lastname: Beaulieu
authors.forename: P C
authors.initials: PC
authors.lastname: Anderson
authors.forename: D R
authors.initials: DR
authors.lastname: Cameron
authors.forename: G
authors.initials: G
authors.lastname: Croteau
authors.forename: V
authors.initials: V
authors.lastname: Gorys
authors.forename: C
authors.initials: C
authors.lastname: Grand-Maître
authors.forename: D
authors.initials: D
authors.lastname: Lamarre
authors.forename: F
authors.initials: F
authors.lastname: Liard
authors.forename: W
authors.initials: W
authors.lastname: Paris
authors.forename: L
authors.initials: L
authors.lastname: Plamondon
authors.forename: F
authors.initials: F
authors.lastname: Soucy
authors.forename: D
authors.initials: D
authors.lastname: Thibeault
authors.forename: D
authors.initials: D
authors.lastname: Wernic
authors.forename: C
authors.initials: C
authors.lastname: Yoakim
authors.forename: S
authors.initials: S
authors.lastname: Pav
authors.forename: L
authors.initials: L
authors.lastname: Tong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D008024:Ligands; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: C102403:BILA 2185 BS; D017320:HIV Protease Inhibitors; D008024:Ligands; D011725:Pyridines