Issue 3, 2022

The identification of highly efficacious functionalised tetrahydrocyclopenta[c]pyrroles as inhibitors of HBV viral replication through modulation of HBV capsid assembly

Abstract

Disruption of the HBV viral life cycle with small molecules that prevent the encapsidation of pregenomic RNA and viral polymerase through binding to HBV core protein is a clinically validated approach to inhibiting HBV viral replication. Herein we report the further optimisation of clinical candidate AB-506 through core modification with a focus on increasing oral exposure and oral half-life. Maintenance of high levels of anti-HBV cellular potency in conjunction with improvements in pharmacokinetic properties led to multi-log10 reductions in serum HBV DNA following low, once-daily oral dosing for key analogues in a preclinical animal model of HBV replication.

Graphical abstract: The identification of highly efficacious functionalised tetrahydrocyclopenta[c]pyrroles as inhibitors of HBV viral replication through modulation of HBV capsid assembly

Supplementary files

Article information

Article type
Research Article
Submitted
30 Sep. 2021
Accepted
17 Jan. 2022
First published
19 Jan. 2022

RSC Med. Chem., 2022,13, 343-349

The identification of highly efficacious functionalised tetrahydrocyclopenta[c]pyrroles as inhibitors of HBV viral replication through modulation of HBV capsid assembly

A. G. Cole, S. G. Kultgen, N. Mani, A. Ardzinski, K. Y. Fan, E. P. Thi, B. D. Dorsey, K. Stever, T. Chiu, S. Tang, O. Daly, J. R. Phelps, T. Harasym, A. Olland, R. K. Suto and M. J. Sofia, RSC Med. Chem., 2022, 13, 343 DOI: 10.1039/D1MD00318F

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