title: Structure-activity relationships of acyloxyamidine cytomegalovirus DNA polymerase inhibitors.
abstract: This paper describes the structure activity relationships of a new class of cytomegalovirus DNA polymerase inhibitors having two aryl groups joined by an acyloxyamidine linker. Examination of a series of analogues in which the terminal groups are varied revealed a very narrow SAR around the 2,4-dichlorophenyl group of the lead compound, but a variety of replacements for the benzothiazole ring are compatible with activity. The most notable of these is the isoxazole ring of compound 78, which provides a 30-fold enhancement in potency compared to the lead compound. We also describe the design, synthesis and evaluation of 10 analogues in which the acyloxyamidine linker is modified or replaced by an isosteric group. Structure-activity relationship studies identified the linker -NH2 group as a critical pharmacophoric element. Ab initio molecular orbital calculations combined with qualitative estimates of steric interaction energies suggest that the lowest energy conformations of the acyloxyamidine linker are characterized by an extended planar CAr-C=N-O-C arrangement and either a syn-periplanar or anti-periplanar N-O-C-C(Ar') arrangement. Only the anti-periplanar conformation was observed in the crystal structures of three acyloxyamidines. The most active of the linker-modified compounds designed on the basis of these studies is the amidine carbamate 20, which is approximately one-third as potent in the cytomegalovirus DNA polymerase inhibition assay as the comparator acyloxyamidine 53. The activity of 20 suggests that acyloxyamidines may bind to the cytomegalovirus DNA polymerase via an anti-periplanar conformation similar to that observed in the crystal structure of acyloxyamidine 36.
authors.affiliation: Discovery Research, Pharmacia and Upjohn, Kalamazoo, MI 49001, USA. btuck@earthlink.net
authors.forename: J A
authors.initials: JA
authors.lastname: Tucker
authors.forename: T L
authors.initials: TL
authors.lastname: Clayton
authors.forename: C G
authors.initials: CG
authors.lastname: Chidester
authors.forename: M W
authors.initials: MW
authors.lastname: Schulz
authors.forename: L E
authors.initials: LE
authors.lastname: Harrington
authors.forename: S J
authors.initials: SJ
authors.lastname: Conrad
authors.forename: Y
authors.initials: Y
authors.lastname: Yagi
authors.forename: N L
authors.initials: NL
authors.lastname: Oien
authors.forename: D
authors.initials: D
authors.lastname: Yurek
authors.forename: M S
authors.initials: MS
authors.lastname: Kuo
mesh_terms: D000578:Amidines / Q000737:chemistry* / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006841:Hydrocarbons, Aromatic / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D019384:Nucleic Acid Synthesis Inhibitors; D012588:Scintillation Counting; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000578:Amidines; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D006841:Hydrocarbons, Aromatic; D019384:Nucleic Acid Synthesis Inhibitors