title: Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design.
abstract: A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, bis tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein-ligand complex of 9 revealed the inhibitor binds in an inverted binding mode relative to 3. Examination of the protein-ligand complex of 9 suggested several modifications in the P1 and P1' pockets. Through these modifications it was possible to improve the activity of the inhibitors another 100-fold, highlighting the utility of crystallographic feedback in inhibitor design. These compounds were found to have good antiviral activity in cell culture, were selective for the HIV protease, and were orally available in three animal models.
authors.affiliation: Agouron Pharmaceuticals Inc. San Diego, California 92121, USA.
authors.forename: M
authors.initials: M
authors.lastname: Melnick
authors.forename: S H
authors.initials: SH
authors.lastname: Reich
authors.forename: K K
authors.initials: KK
authors.lastname: Lewis
authors.forename: L J
authors.initials: LJ
authors.lastname: Mitchell
authors.forename: D
authors.initials: D
authors.lastname: Nguyen
authors.forename: A J
authors.initials: AJ
authors.lastname: Trippe
authors.forename: H
authors.initials: H
authors.lastname: Dawson
authors.forename: J F
authors.initials: JF
authors.lastname: Davies
authors.forename: K
authors.initials: K
authors.lastname: Appelt
authors.forename: B W
authors.initials: BW
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Musick
authors.forename: D K
authors.initials: DK
authors.lastname: Gehlhaar
authors.forename: S
authors.initials: S
authors.lastname: Webber
authors.forename: B
authors.initials: B
authors.lastname: Shetty
authors.forename: M
authors.initials: M
authors.lastname: Kosa
authors.forename: D
authors.initials: D
authors.lastname: Kahil
authors.forename: D
authors.initials: D
authors.lastname: Andrada
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D000882:Haplorhini; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000998:Antiviral Agents; D017320:HIV Protease Inhibitors