Short duration aerosols of JNJ 2408068 (R170591) administered prophylactically or therapeutically protect cotton rats from experimental respiratory syncytial virus infection.
Cotton rats exposed to continuous small droplet aerosols of 2[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]methyl]-6-methyl-3-pyridinol (JNJ 2408068) or its hydrochloric salt for only 15 min, one day prior to virus inoculation or one day after, were significantly protected from pulmonary respiratory syncytial virus (RSV) infection compared to control animals similarly infected but exposed to aerosols of placebo at these times. No evidence of toxicity was seen in any of these animals or in cotton rats administered 10 times the minimum cotton rat efficacious dose (i.e. 10x0.39 mg of active compound per kilogram of body weight) for four continuous days. The marked selective antiviral activity observed in the cotton rats mirrored that seen for these compounds in cytotoxicity and antiviral assays performed against RSV in vitro. Plasma kinetics and tissue distribution of JNJ 2408068 in cotton rats following inhalation were determined in separate experiments performed using conditions similar to those utilized in the in vivo efficacy studies. The data from these experiments indicated that significant levels of the test compound were delivered to the lungs of exposed animals, but that extrapulmonary distribution was limited.
Wyde
Philip R
PR
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. pwyde@bcm.tmc.edu
Chetty
Srikrishna N
SN
Timmerman
Philip
P
Gilbert
Brian E
BE
Andries
Koen
K
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005260:Female; D008168:Lung / Q000378:metabolism / Q000821:virology; D008297:Male; D010880:Piperidines / Q000008:administration & dosage* / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage* / Q000627:therapeutic use; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000517:prevention & control*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000254:growth & development; D016205:Sigmodontinae
C481509:2((2-((1-(2-aminoethyl)-4-piperidinyl)amino)-4-methyl-1H-benzimidazol-1-yl)methyl)-6-methyl-3-pyridinol; D000336:Aerosols; D000998:Antiviral Agents; D001562:Benzimidazoles; D010880:Piperidines; D011725:Pyridines