Measurement Of Single Airway Nerve Fibre Activity To Assess Irritancy Potential Of Inhaled Compound PF-4348235

Optimized glucuronidation of dual pharmacology β-2 agonists/M3 antagonists for the treatment of COPD

“…Indeed, the substitution pattern of the chloro-phenol 15 seemed an optimal balance of metabolic vulnerability and dual pharmacology and this group was retained for further work. Additional structure-activity/metabolism relationships were generated through modification of the B-ring, particularly where the effect of increased lipophilicity may improve metabolic turnover, but this met with limited success (16)(17)(18)(19)(20).…”

“…Additionally, 15 was clean in in vitro genetic toxicity testing (AMES and micronucleus) and was also found to have a clean irritancy profile in a rabbit cough model developed at Sandwich (assessment of Ad-fibre firing in the vagus nerve), giving confidence that it would be a low cough risk in humans. 18 Rat and guinea pig pharmacokinetics experiments on 15, 19 when combined with the poor membrane permeability, metabolic instability, and optimized glucuronidation, predict negligible human oral bioavailability (<5%) thus minimizing potential risks from systemic exposure.…”