ABSTRACT
A series of 8-heteroarylthiomethyldipyridodiazepinone derivatives were prepared and evaluated for their antiviral profile against wild type virus and the important K103N/Y181C mutant as an indicator for broad activity. 2,6-Dimethylpyridine derivative 16 was found to have a good pharmacokinetic profile in spite of poor metabolic stability in rat liver microsomes.
Subject(s)
Anti-HIV Agents , Azepines , HIV Infections/drug therapy , HIV-1/drug effects , Nevirapine/chemical synthesis , Reverse Transcriptase Inhibitors , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacology , Azepines/chemical synthesis , Azepines/metabolism , Azepines/pharmacology , Drug Resistance, Viral , HIV Infections/virology , HIV Reverse Transcriptase/chemistry , HIV-1/enzymology , HIV-1/genetics , Humans , Metabolic Clearance Rate , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Mutation , Nevirapine/pharmacology , Pyridines/chemical synthesis , Pyridines/metabolism , Pyridines/pharmacology , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/metabolism , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Monocyclic beta-lactams have been identified as potent and selective inhibitors of the human cytomegalovirus protease (HCMV) N(o). Two series of these inhibitors are described, a peptidyl series of compounds and non-peptidic molecules featuring lower molecular weights. The SAR work that lead to the discovery of these inhibitors, together with their synthesis is also disclosed.
Subject(s)
Anti-Bacterial Agents/pharmacology , Protease Inhibitors/pharmacology , Serine Endopeptidases/metabolism , Anti-Bacterial Agents/chemistry , Humans , Molecular Weight , Protease Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship , beta-LactamsABSTRACT
The development of peptidomimetic inhibitors of the human cytomegalovirus (HCMV) protease showing sub-micromolar potency in an enzymatic assay is described. Selective substitution of the amino acid residues of these inhibitors led to the identification of tripeptide inhibitors showing improvements in inhibitor potency of 27-fold relative to inhibitor 39 based upon the natural tetrapeptide sequence. Small side chains at P1 were well tolerated by this enzyme, a fact consistent with previous observations. The S2 binding pocket of HCMV protease was very permissive, tolerating lipophilic and basic residues. The substitutions tried at P3 indicated that a small increase in inhibitor potency could be realized by the substitution of a tert-leucine residue for valine. Substitutions of the N-terminal capping group did not significantly affect inhibitor potency. Pentafluoroethyl ketones, alpha,alpha-difluoro-beta-keto amides, phosphonates and alpha-keto amides were all effective substitutions for the activated carbonyl component and gave inhibitors which were selective for HCMV protease. A slight increase in potency was observed by lengthening the P1' residue of the alpha-keto amide series of inhibitors. This position also tolerated a variety of groups making this a potential site for future modifications which could modulate the physicochemical properties of these molecules.
Subject(s)
Antiviral Agents/chemical synthesis , Cytomegalovirus/drug effects , Protease Inhibitors/chemical synthesis , Antiviral Agents/pharmacology , Cytomegalovirus/enzymology , Humans , Protease Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
We have been investigating the potential of a new class of antiviral compounds. These peptidomimetic derivatives prevent association of the two subunits of herpes simplex virus (HSV) ribonucleotide reductase (RR), an enzyme necessary for efficient replication of viral DNA. The compounds disclosed in this paper build on our previously published work. Structure-activity studies reveal beneficial modifications that result in improved antiviral potency in cell culture in a murine ocular model of HSV-induced keratitis. These modifications include a stereochemically defined (2,6-dimethylcyclohexyl)amino N-terminus, two ketomethylene amide bond isosteres, and a (1-ethylneopentyl)amino C-terminus. These three modifications led to the preparation of BILD 1351, our most potent antiherpetic agent containing a ureido N-terminus. Incorporation of the C-terminal modification into our inhibitor series based on a (phenylpropionyl)valine N-terminus provided BILD 1357, a significantly more potent antiviral compound than our previously published best compound, BILD 1263.
