Abstract
PDE4 inhibitors are considered to be potential therapeutic agents that exhibit anti-inflammatory and immuno-modulatory activities. Several PDE4 inhibitors have entered into clinical trials, but showed either lack of efficacy or side effects. We present here the pharmacological and safety profile of a selective PDE4 inhibitor, GRC-3886 with a significantly reduced emetic potential. GRC-3886, a selective PDE4 inhibitor, inhibited human PDE4 enzyme at an IC-50 of 1.4nM and lipopolysaccharide induced TNF-alpha expression with an IC-50 of 190.4nM in HWB assay. GRC-3886 also has shown excellent oral bioavailability, between 50-65% , across the species of animals: mice, rats, monkeys and dogs, tested. GRC-3886 inhibited LPS induced serum TNF-a expression with an ED50 of 1.67 mg/Kg in SD-rats (p < 0.05) and 0.26 mg/kg in Balb/C mice ( p = 0.027) and also inhibited LPS induced pulmonary neutrophilia in S.D.Rats with an ED50 of 1.45 mg/Kg (p < 0.05). GRC-3886 did not induce emesis in ferrets when administered at 100 mg/Kg orally (n= 0/6, mean Cmax = 12.7 micro gram/ml)) nor caused any behavioral changes indicative of an emetic response. GRC-3886 has also been studied in Beagle dogs (n=6) and frank emesis with vomiting of mucus or yellow fluid was noticed in 2 animals (33% incidence) at 30 mg/Kg p.o while no emesis was observed at 20mg/Kg p.o (n=6). GRC-3886 is a safe, novel, orally active PDE4 inhibitor of potential use in the treatment of respiratory diseases.