title: Use of medium-sized cycloalkyl rings to enhance secondary binding: discovery of a new class of human immunodeficiency virus (HIV) protease inhibitors.
abstract: A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800 microM) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, Ki = 0.015 microM) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps).
authors.affiliation: Upjohn Laboratories, Kalamazoo, Michigan 49001, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Romines
authors.forename: K D
authors.initials: KD
authors.lastname: Watenpaugh
authors.forename: P K
authors.initials: PK
authors.lastname: Tomich
authors.forename: W J
authors.initials: WJ
authors.lastname: Howe
authors.forename: J K
authors.initials: JK
authors.lastname: Morris
authors.forename: K D
authors.initials: KD
authors.lastname: Lovasz
authors.forename: A M
authors.initials: AM
authors.lastname: Mulichak
authors.forename: B C
authors.initials: BC
authors.lastname: Finzel
authors.forename: J C
authors.initials: JC
authors.lastname: Lynn
authors.forename: M M
authors.initials: MM
authors.lastname: Horng
mesh_terms: D015110:4-Hydroxycoumarins / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011714:Pyrans / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D015110:4-Hydroxycoumarins; D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D011714:Pyrans; D016333:HIV Protease