The overall aim of this proposal is the development of SB-9000, a novel nucleotide analog, as an orally bioavailable anti-HBV therapeutic agent. The compound was discovered after synthesis, screening, and lead optimization, of a combinatorially-derived library of more than 700 nucleotides as potential inhibitors of HBV replication, using a cell-based assay. The analog displayed high antiviral potency, safety and selectivity indices. The compound inhibits both strands of HBV DNA replication. SB-9000 represents a new, and novel class of anti-HBV compound with demonstrated anti-HBV activity in vitro and efficacy in vivo in an HBV animal model. SB-9000 also shows synergistic anti-HBV activity with 3TC, is active against drug-resistant HBV variants, and has a novel mechanism(s) of action. The proposed studies will be carried out in two phases: Phase I involves (a) Process development for the synthesis of SB-9000, (b) Evaluation of SB-9000 in woodchuck HBV animal model (c) Design, synthesis and evaluation of prodrugs in vitro. Phase II involves (a) Metabolism, oral bioavailability, and pharmacokinetic studies of the prodrugs (b) Evaluation of the prodrugs in transgenic mouse and woodchuck HBV animal models (c) Scale-up and process transfer for GMP manufacture of the prodrug (d) IND-enabling in vitro and in vivo toxicity studies. Four developmental milestones have been set up and are as follows: (1) Process for larger-scale synthesis of SB-9000 (2) Selection of prodrug for in vitro and in vivo studies (3) Identification of orally bioavailable prodrug (4) Completion of IND-enabling studies for the drug candidate. The novel antiviral discovery and development strategy described in the proposal can be applied in the case of other existing and emerging viruses.
| Coughlin, John E; Pandey, Rajendra K; Padmanabhan, Seetharamaiyer et al. (2012) Metabolism, pharmacokinetics, tissue distribution, and stability studies of the prodrug analog of an anti-hepatitis B virus dinucleoside phosphorothioate. Drug Metab Dispos 40:970-81 |
| Coughlin, John E; Padmanabhan, Seetharamaiyer; Zhang, Guangrong et al. (2010) Orally bioavailable anti-HBV dinucleotide acyloxyalkyl prodrugs. Bioorg Med Chem Lett 20:1783-6 |
| Padmanabhan, Seetharamaiyer; Coughlin, John E; Zhang, Guangrong et al. (2006) Anti-HBV nucleotide prodrug analogs: synthesis, bioreversibility, and cytotoxicity studies. Bioorg Med Chem Lett 16:1491-4 |
| Iyer, Radhakrishnan P; Padmanabhan, Seetharamaiyer; Coughlin, John E (2006) Microwave-assisted functionalization of solid supports for rapid loading of nucleosides. Curr Protoc Nucleic Acid Chem Chapter 3:Unit3.13 |
| Iyer, Radhakrishnan P; Padmanabhan, Seetharamaiyer; Zhang, Guangrong et al. (2005) Nucleotide analogs as novel anti-hepatitis B virus agents. Curr Opin Pharmacol 5:520-8 |
| Iyer, Radhakrishnan P; Coughlin, John E; Padmanabhan, Seetharamaiyer (2005) RAPID FUNCTIONALIZATION AND LOADING OF SOLID SUPPORTS. Org Prep Proced Int 37:205-212 |
