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Novel Rho Kinase Inhibitors with Bronchodilator and Anti‐inflammatory Properties Suitable for Treatment of Respiratory Diseases
Author(s) -
Navratil Tomas,
Wells Grace,
Fulcher Emilee,
Sorensen Scott,
Bodnar Wanda,
Crean Chris,
Lampe John,
Peterson Ward
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.756.6
Subject(s) - pharmacology , neutrophilia , bronchodilator , dosing , bioavailability , inflammation , respiratory system , medicine , eosinophilia , chemistry , carbachol , immunology , asthma , receptor
Novel Rho kinase (ROCK) inhibitors were tested for attenuation of airway hyperreactivity (AHR) and pulmonary inflammation. Two distinct profiles of molecules were explored: orally bioavailable molecules, represented by INS117758, suitable for oral product development; and orally nonbioavailable molecules, represented by INS117509, suitable for development as an inhaled product with limited systemic exposure. INS117758 and INS117509 potently inhibit ROCK2 (K i values of 3.8 and 3.3 nM, respectively). While INS117758 is orally bioavailable in rats following 10 mg/kg p.o. dosing (C max = 5.6 μM, T max = 0.83 hours, T 1/2 = 1.55 hours), INS117509 was not detectable in rat plasma following p.o. dosing. INS117758 and INS117509 relaxed carbachol‐precontracted tracheal rings (242 nM and 103 nM IC 50 s, respectively). Dosing of INS117758 p.o. at 5 mg/kg and INS117509 intratracheally (i.t.) at 1.5 mg/kg fully reversed AHR and reduced eosinophilia in OVA‐sensitized mice and neutrophilia in LPS‐exposed mice. In conclusion, Inspire novel ROCK inhibitors are suitable for treatment of respiratory diseases with AHR and pulmonary inflammation via oral route of delivery as well as inhaled route of delivery with limited systemic exposure. Funded by Inspire Pharmaceuticals.