Summary

Name:

TMC353121

Synonyms:

TMC-353121; TMC 353121

Sponsor:

Johnson & Johnson Innovative Medicine / J&J Innovative Medicine (formerly Janssen Therapeutics) (global presence)

Type of product:

Inhibitor

Viral family:

Pneumoviridae

Status:

Preclinical
No further development of the RSV program (Mar. 2023); See Remarks

Structure

Structure TMC353121

Formula:

C32H42N6O3

Molecular weight:

558.71

TMC353121 

Synonyms:TMC-353121; TMC 353121       Sponsor:Johnson & Johnson Innovative Medicine / J&J Innovative Medicine (formerly Janssen Therapeutics) (global presence)       Type of product:Inhibitor       Mode of action:Entry and/or Fusion inhibitor (single agent)       Viral family:Pneumoviridae       Virus:RSV (Respiratory Syncytial virus)      

Details

Characteristics:

Small molecule, morpholinopropylaminobenzimidazole derivative acting as inhibitor of RSV F protein, blocking fusion of viral envelope with cytoplasmic membrane of host cell thereby interfering with viral entry;

 

Because of its lipophilic nature and weak basic properties, cpnd is believed to become trapped in acidic cell compartments (e.g., lysosomes), resulting in high concentrations in lysosome-rich tissues such as those of lung and liver;

 

Analyses of the crystal structure of TMC353121 bound at a hydrophobic pocket of the 6HB formed by amino acid residues from both HR1 and HR2 heptad-repeats of the RSV envelope glycoprotein revealed that the cpnd stabilizes the interaction of HR1 and HR2 in an alternate conformation of the six-helix bundle, in which direct binding interactions are formed between TMC353121 and both HR1 and HR2;
Based on these observations, the cpnd is believed to inhibit fusion of the viral envelope with the cell membrane by causing a local disturbance of the natural six-helix bundle conformation

 

Ref.: Bonfanti JF et al., J Med Chem. 2008 Feb 28;51(4):875-96 (www.ncbi.nlm.nih.gov/pubmed/18254606); Bonfanti &, Roymans. Curr Opin Drug Discov Devel. 2009 Jul;12(4):479-87 (www.ncbi.nlm.nih.gov/pubmed/19562644); Roymans D et al., Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):308-13 (www.ncbi.nlm.nih.gov/pubmed/19966279)

 

PK Data, Dosage or Route of Administration:

After oral administration of the cpnd to Sprague-Dawley rats, the plasma drug concentration-time profile of TMC353121 exhibited multicompartmental PK;

  • Mean plasma drug concentrations decreased rapidly during the first hours after dosing and then more slowly (T½ = approx 12 h)
  • Rapid elimination from plasma (CL = 8.6 liters/h/kg)
  • Product extensively distributed (Vss = 55 liters/kg)
  • Lung tissue drug concentrations were much higher than plasma drug concentrations (lung-to-plasma AUC0-24 h ratio, 122)

 

Ref.: Rouan MC et al., Antimicrob Agents Chemother. 2010 Nov;54(11):4534-9 (www.ncbi.nlm.nih.gov/pubmed/20823290)

 

In vivo and clinical data:

In animal studies, cotton rats received nanocrystal formulation of cpnd in s.c. doses of 12.5, 25, 50, 100, and 200 mg/kg 24 h before virus inoculation;

Four days later, bronchoalveolar lavage fluid samples were collected and RSV titers were determined by plaque and qRT-PCR assays;

Viral load in untreated control animals was 5.6 log10 PFU/ml of lung epithelial lining fluid;

Compared to titers of untreated control rats, significant (P values < 0.05) reductions of 0.2, 0.3, 0.4, 0.8, and 1.2 log10 PFU/ml of lung epithelial lining fluid were measured by plaque assay and of 0.5, 0.6, 1.1, 1.7, and 2.2 log10 PFU/ml of lung epithelial lining fluid were measured by qRT-PCR assay after administration of above-mentioned doses, respectively

 

Ref.: Rouan MC et al., Antimicrob Agents Chemother. 2010 Nov;54(11):4534-9 (www.ncbi.nlm.nih.gov/pubmed/20823290)

 

 

Activity in vitro

EC50: 0.125 nM (0.07 ng/mL)(RSV LO strain, HeLa cells)



Ref.: Bonfanti JF et al., J Med Chem. 2008 Feb 28;51(4):875-96 (www.ncbi.nlm.nih.gov/pubmed/18254606)

 

Development status

Preclinical
No further development of the RSV program (Mar. 2023); See Remarks

Remarks

Novel cpnd for potential treatment of RSV infection;

 

On Mar. 29, 2023, the Janssen Pharmaceutical Companies of Johnson & Johnson disclosed that following a review of its portfolio to prioritize the most transformational assets for ongoing investment, and an assessment of the RSV vaccine landscape, the Company will exit its investigational RSV adult vaccine program and discontinue its Phase III EVERGREEN study.
The decision to discontinue the Company’s RSV adult vaccine program is part of a broader effort to make strategic choices for its pipeline and research and development (R&D) investments to focus on medicines with the greatest potential benefit to patients.
[www.janssen.com/janssen-provides-portfolio-update] ; [www.prnewswire.com/news-releases/janssen-provides-portfolio-update-301784001.html]



Formula: C32H42N6O3
Molecular weight: 558.71