Antiviral InteliStrat Inc.

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)

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 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)

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)