Vijay Urmaliya

Identification and Optimization of Pyrrolo[3,2- d ]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B

Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug. Oral administration of the lead compound 54 effectively induced a transient interferon stimulated gene (ISG) response in mice and cynomolgus monkeys. We aimed for a high first pass effect, limiting cytokine induction systemically, and demonstrated the potential for the immunotherapy of viral hepatitis.

Evaluation of cardiac electrophysiology (ECG), heart rate and index of cardiac electrophysiological balance (iCEB) during basal condition in awake telemetered and anesthetized guinea pigs

CO RR EC TE D P RO OF stability and fidelity of the signals were excellent over time.When rats were resting quietly, a strong respiratory rhythm was seen in both signals. At the end of the study, the rats were lightly anesthetised with isofluorane and subjected to a head up and head down tilt tests to 45° resulting in reversible decreases and increases of ICP as expected. No visible damaged from the ICP catheter was found on the brain surface at post-mortem.