A Double-Blind, Randomized, Placebo-Controlled, Single and Multiple Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AB-452 Following Oral Administration in Healthy Subjects and Subjects with Chronic Hepatitis B

Start Date08 Oct 2018

Sponsor / Collaborator

Arbutus Biopharma Corp.

100 Clinical Results associated with AB-452

100 Translational Medicine associated with AB-452

100 Patents (Medical) associated with AB-452

Literatures (Medical) associated with AB-452

25 Jan 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Structure–Activity Relationships and Discovery of (S)-6-Isopropyl-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic Acid (AB-452), a Novel Orally Available HBV RNA Destabilizer

Q1 · MEDICINE

Article

Author: Chiu, Tim ; Liu, Fei ; Harasym, Troy ; Tang, Sunny ; Dorsey, Bruce D. ; Lee, Amy C.-H. ; Chen, Shuai ; Gotchev, Dimitar ; Nguyen, Duyan ; Gao, Min ; Sofia, Michael J. ; Kakarla, Ramesh ; Dugan, Benjamin ; Cole, Andrew G. ; Bailey, Laurèn

Approved therapies for hepatitis B virus (HBV) treatment include nucleos(t)ides and interferon alpha (IFN-α) which effectively suppress viral replication, but they rarely lead to cure. Expression of viral proteins, especially surface antigen of the hepatitis B virus (HBsAg) from covalently closed circular DNA (cccDNA) and the integrated genome, is believed to contribute to the persistence of HBV. This work focuses on therapies that target the expression of HBV proteins, in particular HBsAg, which differs from current treatments. Here we describe the identification of AB-452, a dihydroquinolizinone (DHQ) analogue. AB-452 is a potent HBV RNA destabilizer by inhibiting PAPD5/7 proteins in vitro with good in vivo efficacy in a chronic HBV mouse model. AB-452 showed acceptable tolerability in 28-day rat and dog toxicity studies, and a high degree of oral exposure in multiple species. Based on its in vitro and in vivo profiles, AB-452 was identified as a clinical development candidate.

Journal of Medicinal Chemistry

Structure–Activity Relationships and Discovery of (S)-5-(tert-Butyl)-11-(difluoromethoxy)-9-methoxy-2-oxo-1,2,5,6-tetrahydropyrido[2′,1′:2,3]imidazo[4,5-h]quinoline-3-carboxylic Acid (AB-161), a Novel Orally Available and Liver-Centric HBV RNA Destabilizer

Article

Author: Graves, Ingrid E. ; Chiu, Tim ; Dugyala, Ravi ; Dugan, Benjamin ; Chen, Shuai ; Wang, Xu ; Tang, Sunny ; Mason, Jeremy D. ; Sofia, Michael J. ; Liu, Fei ; Kowalski, Rose ; Overholt, Nathan ; Thi, Emily P. ; Cole, Andrew G. ; Gotchev, Dimitar ; Lam, Angela M. ; Dorsey, Bruce D. ; Sheraz, Muhammad ; Harasym, Troy

Lowering hepatitis B surface antigen (HBsAg) levels from covalently closed circular DNA (cccDNA) and the integrated genome could reduce the persistence of hepatitis B virus (HBV) infection. Since HBV replication occurs in the liver and to ameliorate the peripheral neuropathy observed with a first-generation tricyclic 4-pyridone PAPD5/7 inhibitor (AB-452) having high systemic exposure, we focused on increasing the hepatocyte concentration and reducing plasma levels. Optimization of a novel series of PAPD5/7 inhibitors that decrease HBsAg levels led to the tetracyclic 2-pyridone AB-161, which was similarly potent to AB-452 in vitro and in vivo but showed dramatically higher rodent liver-to-plasma ratios. There were no neurobehavioral effects with AB-161 in dogs up to 45 mg/kg after 60 days, unlike with AB-452, where these were observed at lower doses by day 14. AB-161 was then advanced into 90-day GLP toxicology studies, where the improved neurotoxicity profile persisted, but reproductive issues emerged, leading to discontinuation.

100 Deals associated with AB-452

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis B	Preclinical	US	Arbutus Biopharma Corp.	-
Hepatitis B	Preclinical	-	Alumni Association Of Drexel University College Of Medicine	-
Hepatitis B	Preclinical	-	Baruch S. Blumberg Institute	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

AB-452

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation