title: Cycloalkylpyranones and cycloalkyldihydropyrones as HIV protease inhibitors: exploring the impact of ring size on structure-activity relationships.
abstract: Previously, 3-substituted cycloalkylpyranones, such as 2d, have proven to be effective inhibitors of HIV protease. In an initial series of 3-(1-phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We became interested in exploring the influence of other structural changes, such as substitution on the phenyl ring and saturation of the 5,6-double bond, on the cycloalkyl ring size structure-activity relationship (SAR). Saturation of the 5,6-double bond in the pyrone ring significantly impacts the SAR, altering the optimal ring size from eight to six. Substitution of a sulfonamide at the meta position of the phenyl ring dramatically increases the potency of these inhibitors, but it does not change the optimal ring size in either the cycloalkylpyranone or the cycloalkyldihydropyrone series. This work has led to the identification of compounds with superb binding affinity for the HIV protease (Ki values in the 10-50 pM range). In addition, the cycloalkyldihydropyrones showed excellent antiviral activity in cell culture, with ED50 values as low as 1 microM.
authors.affiliation: Pharmacia and Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Romines
authors.forename: J K
authors.initials: JK
authors.lastname: Morris
authors.forename: W J
authors.initials: WJ
authors.lastname: Howe
authors.forename: P K
authors.initials: PK
authors.lastname: Tomich
authors.forename: M M
authors.initials: MM
authors.lastname: Horng
authors.forename: K T
authors.initials: KT
authors.lastname: Chong
authors.forename: R R
authors.initials: RR
authors.lastname: Hinshaw
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: J W
authors.initials: JW
authors.lastname: Strohbach
authors.forename: S R
authors.initials: SR
authors.lastname: Turner
authors.forename: S A
authors.initials: SA
authors.lastname: Mizsak
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003500:Cyclization; D016333:HIV Protease; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D011753:Pyrones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011753:Pyrones; D013449:Sulfonamides; C101739:5,6,7,8,9,10-hexahydro-4-hydroxy-3-(1-phenylpropyl)-2H-cycloocta(b)pyran-2-one; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease; C065184:p16 protease, Human immunodeficiency virus 2