Use of the oxadiazolone acid isostere in triiodothyronine analogs yielded potent and selective agonists for the thyroid hormone receptor ß. Selected examples showed good in-vivo efficacy in a rat hypercholesterolemic model. One compound was further profiled in a diet-induced mouse model of nonalcoholic steatohepatitis (NASH) and showed robust target engagement and significant histological improvements in both liver steatosis and fibrosis.
Oxadiazoles/pharmacology , Thyroid Hormone Receptors beta/agonists , Animals , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C57BL , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Nucleosides/chemistry , Nucleosides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Animals , Antiviral Agents/pharmacokinetics , Caco-2 Cells , Cell Line , Cricetinae , Drug Discovery , Drug Resistance, Viral , Halogenation , Hepacivirus/genetics , Hepacivirus/physiology , Hepatitis C/drug therapy , Humans , Methylation , Molecular Docking Simulation , Nucleosides/pharmacokinetics , Phosphoric Acids/chemistry , Phosphoric Acids/pharmacokinetics , Phosphoric Acids/pharmacology , Point Mutation , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
Ribose modified 1'-C-cyano pyrimidine nucleosides were synthesized. A silver triflate mediated Vorbrüggen reaction was used to generate the nucleoside scaffold and follow-up chemistry provided specific ribose modified analogs. Nucleosides and phosphoramidate prodrugs were tested for their anti-HCV activity.
DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacology , Chemistry Techniques, Synthetic , Enzyme Inhibitors/chemistry , Pyrimidine Nucleosides/chemistry
The first synthesis of 1'-C-CN, 2'-F, 2'-C-Me pyrimidines is described. Anti-HCV activity was assessed and compared to the 1'-C-CN, 2'-C-Me as well as the 2'-F, 2'-C-Me pyrimidines. A phosphoramidate prodrug of the cytidine derivative showed activity in the low micromolar range against HCV replicons.
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacology , Amides/chemistry , Amides/pharmacology , Cell Line , Halogenation , Hepacivirus/enzymology , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Methylation , Phosphoric Acids/chemistry , Phosphoric Acids/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Replicon/drug effects
A sulfonamide replacement of the P2-P3 amide bond in the context of macrocyclic HCV NS3 protease inhibitors was investigated. These analogs displayed good inhibitory potency in the absence of any P3 capping group. The synthesis and preliminary SAR are described.
Hepacivirus/drug effects , Sulfonamides/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Molecular Structure , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Structure-Activity Relationship , Sulfonamides/pharmacology
HIV-1 RNase H breaks down the intermediate RNA-DNA hybrids during reverse transcription, requiring two divalent metal ions for activity. Pyrimidinol carboxylic acid and N-hydroxy quinazolinedione inhibitors were designed to coordinate the two metal ions in the active site of RNase H. High-resolution (1.4 Å to 2.1 Å) crystal structures were determined with the isolated RNase H domain and reverse transcriptase (RT), which permit accurate assessment of the metal and water environment at the active site. The geometry of the metal coordination suggests that the inhibitors mimic a substrate state prior to phosphodiester catalysis. Surface plasmon resonance studies confirm metal-dependent binding to RNase H and demonstrate that the inhibitors do not bind at the polymerase active site of RT. Additional evaluation of the RNase H site reveals an open protein surface with few additional interactions to optimize active-site inhibitors.
Anti-HIV Agents/pharmacology , HIV-1/drug effects , Pyrimidines/pharmacology , Quinazolinones/pharmacology , Ribonuclease H/antagonists & inhibitors , Amino Acid Sequence , Crystallization , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/chemistry , HIV-1/enzymology , Molecular Conformation , Molecular Sequence Data , Pyrimidines/chemistry , Quinazolinones/chemistry , Ribonuclease H/chemistry , Structure-Activity Relationship
Pyrimidinol carboxylic acids were designed as inhibitors of HIV-1 RNase H function. These molecules can coordinate to two divalent metal ions in the RNase H active site. Inhibition of enzymatic activity was measured in a biochemical assay, but no antiviral effect was observed. Binding was demonstrated via a solid state structure of the isolated p15-Ec domain of HIV-1 RT showing inhibitor and two Mn(II) ions bound to the RNase H active site.
HIV Reverse Transcriptase/antagonists & inhibitors , Pyrimidines/pharmacology , Ribonuclease H/antagonists & inhibitors , Carboxylic Acids , Catalytic Domain , Drug Design , Humans , Protein Binding , Pyrimidines/chemistry
A series of 3,4,5-trisubstituted 1,2,4-4H triazole derivatives was synthesized and investigated for HIV-1 reverse transcriptase inhibition. An X-ray structure with HIV-1 RT secured the binding mode and allowed the key interactions with the enzyme to be identified.
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Anti-HIV Agents/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Molecular Conformation , Molecular Structure , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity Relationship , Triazoles/chemistry
[structure: see text] A flexible and efficient procedure has been developed for the conjugation of taxol to various arginine-based molecular transporters via the taxol C2' O-chloroacetyl derivative. The resultant taxol-transporter conjugates are highly water soluble and release free taxol with half-lives of minutes to hours depending on the pH and the linker structure.
Antineoplastic Agents/chemical synthesis , Arginine/analogs & derivatives , Membrane Transport Proteins/chemical synthesis , Paclitaxel/chemistry , Acetylation , Half-Life , Hydrogen-Ion Concentration , Molecular Structure , Solubility , Stereoisomerism
