Unexpected neurotoxicity in chronic toxicity studies with a HBV viral expression inhibitor

Bopst, Martin; Dinklo, Theo; Funk, Juergen; Greiter‐Wilke, Andrea; Lenz, Barbara; Kustermann, Stefan; Jiang, Tianyi; Xie, Jianxun

doi:10.1016/j.yrtph.2023.105407

Cited by 7 publications

(15 citation statements)

References 14 publications

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“…Despite intense interest from groups across the pharmaceutical industry, it appears that none have successfully advanced a compound from this class beyond Phase I clinical trials in humans. Similar findings in cynomolgous were reported for molecule from a distinct chemical series, a tetrahydropyridopyrimidine . As such, we suspect that on-target toxicity, perpetrated by PAPD5/7 inhibition, will render efforts to suppress HBsAg by this mechanism of action challenging.…”

supporting

confidence: 77%

“…Emerging from this class, RG7834 ( 4 , Table ) demonstrated viral antigen suppression in mouse and woodchuck models of HBV infection. After briefly entering Phase 1 clinical trials, RG7834 was withdrawn due to neurotoxicity liabilities . Related findings reported for structurally differentiated inhibitors of PAPD5/7 suggest the toxicity is on-target, although the precise mechanism remains undetermined.…”

mentioning

confidence: 99%

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Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873

Kato,

Choy,

Canales

et al. 2024

ACS Med. Chem. Lett.

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Chronic hepatitis B (CHB) virus infection afflicts hundreds of millions of people and causes nearly one million deaths annually. The high levels of circulating viral surface antigen (HBsAg) that characterize CHB may lead to T-cell exhaustion, resulting in an impaired antiviral immune response in the host. Agents that suppress HBsAg could help invigorate immunity toward infected hepatocytes and facilitate a functional cure. A series of dihydropyridoisoquinolizinone (DHQ) inhibitors of human poly(A) polymerases PAPD5/7 were reported to suppress HBsAg in vitro. An example from this class, RG7834, briefly entered the clinic. We set out to identify a potent, orally bioavailable, and safe PAPD5/7 inhibitor as a potential component of a functional cure regimen. Our efforts led to the identification of a dihydropyridophthalazinone (DPP) core with improved pharmacokinetic properties. A conformational restriction strategy and optimization of core substitution led to GS-8873, which was projected to provide deep HBsAg suppression with once-daily dosing.

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supporting

confidence: 77%

mentioning

confidence: 99%

Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873

Kato,

Choy,

Canales

et al. 2024

ACS Med. Chem. Lett.

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“…Similar to our findings, significant nerve conduction velocity (NCV) decreases and latency increases were observed with the structurally related GS-8873 after dosing in rats and monkeys for 4 weeks . More recently, polyneuropathy after repeat dosing in monkeys was also reported for RG7834 . The optimization of our series of analogues to address the peripheral neuropathy adverse events will be reported in due course.…”

Section: Discussionmentioning

confidence: 99%

“…Despite a NOAEL of 150 mg/kg/day and 30 mg/kg/day in 28-day rat and dog toxicity studies, respectively, further progression was halted after the observation of 31 More recently, polyneuropathy after repeat dosing in monkeys was also reported for RG7834. 32 The optimization of our series of analogues to address the peripheral neuropathy adverse events will be reported in due course.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.54 (s, 1H), 7.74 (s, 1H), 7.45−7.32 (m, 5H), 7.20 (s, 1H), 6.57 (s, 1H), 5.25 (s, 2H), 4.37 (q, J = 2.4 Hz, 2H), 3.85 (s, 3H), 1.30 (t, J = 2.4 Hz, 3H). (32). To a solution of ethyl 6-(2-(benzyloxy)-5-chloro-4-methoxyphenyl)-4-oxo-4H-pyran-3-carboxylate 31 (208 mg, 0.5 mmol) in glacial AcOH (4 mL) and EtOH (6 mL) was added DL-valinol (0.08 mL, 0.75 mmol).…”

Section: S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-6-methyl-10...mentioning

confidence: 99%

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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

Gotchev,

Dorsey,

Nguyen

et al. 2024

J. Med. Chem.

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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.

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A revolutionary oral HBV treatment candidate as innovative therapeutic approach warranting clinical trials

Matsui

2024

J Gastroenterol

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Unexpected neurotoxicity in chronic toxicity studies with a HBV viral expression inhibitor

Cited by 7 publications

References 14 publications

Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873

Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873

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

A revolutionary oral HBV treatment candidate as innovative therapeutic approach warranting clinical trials

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