JNJ-4796

Description

APIM050411: JNJ-4796 is an oral active fusion inhibitor of influenza virus, neutralizing influenza A group 1 viruses by inhibiting hemagglutinin (HA)-mediated fusion. JNJ-4796 mimics the functionality of the broadly neutralizing antibodies (bnAbs).

CAS No.: 2241664-16-2
IUPAC/Chemical Name: (R)-N-(2-(2-(4-((2-methyl-2H-tetrazol-5-yl)(phenyl)methyl)piperazine-1-carbonyl)pyridin-4-yl)benzo[d]oxazol-5-yl)acetamide
Molecular Formula: C₂₈H₂₇N₉O₃
Molecular Weight: 537.58
Purity: >98% Purity
QC: Achiral and Chiral HPLCs, MS, NMR, and Quantitative Elemental Analysis Report
Solubility: Soluble in DMSO
Storage: Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).
Note: Please contact us for COA, Spectra, and SDS information.

Background Information:

The World Health Organization estimates that influenza epidemics cause approximately 3 million to 5 million cases of severe illness. What’s worse, up to 650,000 people died worldwide each year. Recently, emerge studies have characterized broadly neutralizing antibodies (bnAbs) as an effective therapeutic option for influenza virus infected patients. Because the target hemagglutinin (HA) stem, identified by bnAbs is conserved. As we all know, antibodies are generally unsuited for oral delivery.

JNJ-4796 (CAS No. 2241664-16-2) showed effective anti-virus activity. The fusion inhibitor is identified as an oral active fusion inhibitor of influenza virus, neutralizing influenza A group 1 viruses by inhibiting hemagglutinin (HA)-mediated fusion, with EC₅₀ values of 12 nM, 66 nM, 38 nM, 22 nM, 13 nM, 449 nM and 3.24 μM for H1/Bris, H1/Cal, H1/NCa, H1/PR8, H1/SI06, H5/H97 and H5/Viet, respectively.

Furthermore, oral administration of JNJ-4796 could protect mice from lethal challenge of 25 times the median lethal dose (LD50) of H1N1 A/Puerto Rico/8/1934 virus. Doses of 50 and 10 mg/kg of JNJ4796 twice daily resulted in 100% survival at day 21. In addition, JNJ-4796 resulted in dose-dependent efficacy. The dosage of 15 and 5 mg/kg of JNJ-4796 twice daily gave rise to 100% survival.

JNJ-4796 provides a possibility for influenza virus therapy. The novel compound also has potential to be a promising clinical drug recapitulates the bnAb hotspot interactions.

Target: H1/Bris, H1/Cal, H1/NCa, H1/PR8, H1/SI06, H5/H97, H5/Viet

EC₅₀: 12 nM (H1/Bris), 66 nM (H1/Cal), 38 nM (H1/NCa), 22 nM (H1/PR8), 13 nM (H1/SI06), 449 nM (H5/H97), 3.24 μM (H5/Viet)

In Vitro: Like bnAb CR6261, the mechanism of action of JNJ-4796 (CAS 2241664-16-2) is demonstrated to be based on inhibition of the pH-sensitive conformational change of HA that triggers fusion of the viral and endosomal membranes and release of the viral genome into the host cell. [1]

In Vivo: Oral administration of JNJ-4796 (CAS 2241664-16-2) protects mice from lethal challenge of 25 times the median lethal dose (LD50) of H1N1 A/Puerto Rico/8/1934 virus. Doses of 50 and 10 mg/kg of JNJ-4796 twice daily, initiated one day before challenge and continuing for 7 days, results in 100% survival at day 21 in comparison to the less potent compound JNJ8897 for which less than 50% survival is achieved. [1]
Oral doses of JNJ4796 results in dose-dependent efficacy after a sublethal viral challenge (LD90), with twice daily administration of 15 and 5 mg/kg of JNJ-4796 giving rise to 100% survival. [1]

What is the solubility of JNJ-4796 in vitro?
DMSO: > 100 mg/mL

What is the solubility of JNJ-4796 in vivo?
1. DMSO, PEG300, Tween-80, saline
Please add DMSO (10%), PEG300 (40%), Tween-80 (5%), saline (45%) in order, solubility ≥ 2.5 mg/mL.
2. DMSO, 20% SBE-β-CD in saline
Please add 10% DMSO and 90% (20% SBE-β-CD in saline) in order, solubility: ≥ 2.5 mg/mL.
3. DMSO, corn oil
Please add 10% DMSO and 90% corn oil in order, solubility: ≥ 2.5 mg/mL.

Reference:
[1]. van Dongen, M. J. P. et al. “A small-molecule fusion inhibitor of influenza virus is orally active in mice”, Science, 2019, 363, eaar6221. doi: 10.1126/science.aar6221.
[2]. Yao, Y. et al. “An influenza A hemagglutinin small-molecule fusion inhibitor identified by a new high-throughput fluorescence polarization screen”, Proc. Natl. Acad. Sci. U. S. A., 2020, 117, 18431-18438
[3]. Wang, A. et al. “Optimization and SAR research at the piperazine and phenyl rings of JNJ4796 as new anti-influenza A virus agents, part 1”, Eur. J. Med. Chem. 2021, 222, 113591.

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Additional information

Size	10 mg, 100 mg, 5 mg, 50 mg

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