The in Vivo Profile of CT133, a Potent, Well Tolerated, and Selective CRTH2 Antagonist for the Treatment of Allergic Asthma and Rhinitis

Abstract

RationaleCT133 is a novel selective receptor antagonist of CRTH2, a potential target for treatment of asthma, allergic rhinitis and obstructive pulmonary diseases.MethodsPreclinical studies using albumin-induced allergic asthma and rhinitis mice models were performed.ResultsSerum results demonstrated that CT133 significantly inhibits the concentration of serum total IL-5, anti-OVA-IgE, and therefore improves the slow respiration symptom of allergic rhinitis, heightens respiratory frequency, and reduces the frequency of sneeze. After a single oral administration, the bioavailability in mice, rat and dog is 89.6%, 71.6% and 85.4%, respectively. There is no significant difference in T1/2, Cmax, Cmin and AUCinf between the first day and the seventh day after oral repeated administration in rats. No drug accumulation was detected, indicating the drug has no inducing effect on metabolic enzymes. CT133 demonstrated excellent safety profile in preclinical studies. No adverse reaction was detected in rat single oral administration assay (300, 1000, 2000mg/kg/day), dog single oral administration assay (100, 300, 1000mg/kg/day), and dog 7-day oral administration assay (100mg/kg/day). The NOAEL of CT133 in rat or dog single oral administration is 300mg/kg.ConclusionsCT133 represents a novel, potent and well-tolerated drug candidate for etiological treatment of allergic asthma and rhinitis. RationaleCT133 is a novel selective receptor antagonist of CRTH2, a potential target for treatment of asthma, allergic rhinitis and obstructive pulmonary diseases. CT133 is a novel selective receptor antagonist of CRTH2, a potential target for treatment of asthma, allergic rhinitis and obstructive pulmonary diseases. MethodsPreclinical studies using albumin-induced allergic asthma and rhinitis mice models were performed. Preclinical studies using albumin-induced allergic asthma and rhinitis mice models were performed. ResultsSerum results demonstrated that CT133 significantly inhibits the concentration of serum total IL-5, anti-OVA-IgE, and therefore improves the slow respiration symptom of allergic rhinitis, heightens respiratory frequency, and reduces the frequency of sneeze. After a single oral administration, the bioavailability in mice, rat and dog is 89.6%, 71.6% and 85.4%, respectively. There is no significant difference in T1/2, Cmax, Cmin and AUCinf between the first day and the seventh day after oral repeated administration in rats. No drug accumulation was detected, indicating the drug has no inducing effect on metabolic enzymes. CT133 demonstrated excellent safety profile in preclinical studies. No adverse reaction was detected in rat single oral administration assay (300, 1000, 2000mg/kg/day), dog single oral administration assay (100, 300, 1000mg/kg/day), and dog 7-day oral administration assay (100mg/kg/day). The NOAEL of CT133 in rat or dog single oral administration is 300mg/kg. Serum results demonstrated that CT133 significantly inhibits the concentration of serum total IL-5, anti-OVA-IgE, and therefore improves the slow respiration symptom of allergic rhinitis, heightens respiratory frequency, and reduces the frequency of sneeze. After a single oral administration, the bioavailability in mice, rat and dog is 89.6%, 71.6% and 85.4%, respectively. There is no significant difference in T1/2, Cmax, Cmin and AUCinf between the first day and the seventh day after oral repeated administration in rats. No drug accumulation was detected, indicating the drug has no inducing effect on metabolic enzymes. CT133 demonstrated excellent safety profile in preclinical studies. No adverse reaction was detected in rat single oral administration assay (300, 1000, 2000mg/kg/day), dog single oral administration assay (100, 300, 1000mg/kg/day), and dog 7-day oral administration assay (100mg/kg/day). The NOAEL of CT133 in rat or dog single oral administration is 300mg/kg. ConclusionsCT133 represents a novel, potent and well-tolerated drug candidate for etiological treatment of allergic asthma and rhinitis. CT133 represents a novel, potent and well-tolerated drug candidate for etiological treatment of allergic asthma and rhinitis.