ABSTRACT
DNA viruses are responsible for many diseases in humans. Current treatments are often limited by toxicity, as in the case of cidofovir (CDV, Vistide), a compound used against cytomegalovirus (CMV) and adenovirus (AdV) infections. CDV is a polar molecule with poor bioavailability, and its overall clinical utility is limited by the high occurrence of acute nephrotoxicity. To circumvent these disadvantages, we designed nine CDV prodrug analogues. The prodrugs modulate the polarity of CDV with a long sulfonyl alkyl chain attached to one of the phosphono oxygens. We added capping groups to the end of the alkyl chain to minimize ß-oxidation and focus the metabolism on the phosphoester hydrolysis, thereby tuning the rate of this reaction by altering the alkyl chain length. With these modifications, the prodrugs have excellent aqueous solubility, optimized metabolic stability, increased cellular permeability, and rapid intracellular conversion to the pharmacologically active diphosphate form (CDV-PP). The prodrugs exhibited significantly enhanced antiviral potency against a wide range of DNA viruses in infected human foreskin fibroblasts. Single-dose intravenous and oral pharmacokinetic experiments showed that the compounds maintained plasma and target tissue levels of CDV well above the EC50 for 24 h. These experiments identified a novel lead candidate, NPP-669. NPP-669 demonstrated efficacy against CMV infections in mice and AdV infections in hamsters following oral (p.o.) dosing at a dose of 1 mg/kg BID and 0.1 mg/kg QD, respectively. We further showed that NPP-669 at 30 mg/kg QD did not exhibit histological signs of toxicity in mice or hamsters. These data suggest that NPP-669 is a promising lead candidate for a broad-spectrum antiviral compound.
Subject(s)
Cytomegalovirus Infections , Organophosphonates , Prodrugs , Mice , Humans , Animals , Antiviral Agents/pharmacokinetics , Biological Availability , Prodrugs/pharmacology , Cytosine , CidofovirABSTRACT
Through a phenotypic high-throughput screen using a serum response element luciferase promoter, we identified a novel 5-aryl-1,3,4-oxadiazol-2-ylthiopropionic acid lead inhibitor of Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF)-mediated gene transcription with good potency (IC50 = 180 nM). We were able to rapidly improve the cellular potency by 5 orders of magnitude guided by sharply defined and synergistic SAR. The remarkable potency and depth of the SAR, as well as the relatively low molecular weight of the series, suggests, but does not prove, that binding to the unknown molecular target may be occurring through a covalent mechanism. The series nevertheless has no observable cytotoxicity up to 100 µM. Ensuing pharmacokinetic optimization resulted in the development of two potent and orally bioavailable anti-fibrotic agents that were capable of dose-dependently reducing connective tissue growth factor gene expression in vitro as well as significantly reducing the development of bleomycin-induced dermal fibrosis in mice in vivo.
Subject(s)
Carboxylic Acids/therapeutic use , Enzyme Inhibitors/therapeutic use , Fibrosis/drug therapy , Oxadiazoles/therapeutic use , Serum Response Factor/antagonists & inhibitors , Trans-Activators/antagonists & inhibitors , Animals , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacokinetics , Connective Tissue Growth Factor/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Female , Fibrosis/pathology , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Scleroderma, Systemic/drug therapy , Scleroderma, Systemic/pathology , Signal Transduction/drug effects , Skin/pathology , Structure-Activity Relationship , Transcription, Genetic/drug effects , rho GTP-Binding Proteins/antagonists & inhibitorsABSTRACT
We recently reported the development of a novel inhibitor of Rho-mediated gene transcription (1, CCG-203971) that is efficacious in multiple animal models of acute fibrosis, including scleroderma, when given intraperitoneally. The modest in vivo potency and poor pharmacokinetics (PK) of this lead, however, make it unsuitable for long term efficacy studies. We therefore undertook a systematic medicinal chemistry effort to improve both the metabolic stability and the solubility of 1, resulting in the identification of two analogs achieving over 10-fold increases in plasma exposures in mice. We subsequently showed that one of these analogs (8f, CCG-232601) could inhibit the development of bleomycin-induced dermal fibrosis in mice when administered orally at 50mg/kg, an effect that was comparable to what we had observed earlier with 1 at a 4-fold higher IP dose.
Subject(s)
Nipecotic Acids/pharmacokinetics , Nipecotic Acids/therapeutic use , Rho Factor/antagonists & inhibitors , Scleroderma, Systemic/drug therapy , Skin/drug effects , Transcriptional Activation/drug effects , Administration, Oral , Animals , Disease Models, Animal , Fibrosis , HEK293 Cells , Humans , Mice , Nipecotic Acids/administration & dosage , Nipecotic Acids/chemistry , Rho Factor/metabolism , Scleroderma, Systemic/genetics , Scleroderma, Systemic/metabolism , Scleroderma, Systemic/pathology , Serum Response Element/drug effects , Skin/metabolism , Skin/pathology , Trans-Activators/antagonists & inhibitors , Trans-Activators/metabolismABSTRACT
A series of benzyl phenyl ethers (BPEs) is described that displays potent inhibition of bacterial phenylalanyl-tRNA synthetase. The synthesis, SAR, and select ADMET data are provided.
Subject(s)
Bacteria/enzymology , Chemistry, Pharmaceutical/methods , Phenyl Ethers/chemistry , Phenylalanine-tRNA Ligase/chemistry , Adenosine Triphosphate/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Drug Design , Drug Evaluation, Preclinical/methods , Inhibitory Concentration 50 , Models, Chemical , Structure-Activity RelationshipABSTRACT
A novel series of bacterial topoisomerase (3-aminoquinazolinediones) inhibitors are described. The side-chain SAR against Gram-positive and Gram-negative organisms as well as DNA gyrase activity is reported.