title: Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands.
abstract: A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratory, West Point, Pennsylvania 19486.
authors.forename: A K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: W J
authors.initials: WJ
authors.lastname: Thompson
authors.forename: M K
authors.initials: MK
authors.lastname: Holloway
authors.forename: S P
authors.initials: SP
authors.lastname: McKee
authors.forename: T T
authors.initials: TT
authors.lastname: Duong
authors.forename: H Y
authors.initials: HY
authors.lastname: Lee
authors.forename: P M
authors.initials: PM
authors.lastname: Munson
authors.forename: A M
authors.initials: AM
authors.lastname: Smith
authors.forename: J M
authors.initials: JM
authors.lastname: Wai
authors.forename: P L
authors.initials: PL
authors.lastname: Darke
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors