β₂-adrenoreceptor is a kind of β-adrenergic receptor across the cell membrane, which binds to adrenaline. Specifically, Adrenaline is a kind of hormone and neurotransmitter and it can enhance the signal by the stimulation of adenosine cyclase by Gs protein. Besides, β₂-adrenoreceptor agonists are a highly pioneering class of drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Moreover, respiratory diseases, such as asthma and copda, are highly prevalent. At present, the main focus of the respiratory field is to identify novel long-acting β₂-adrenoreceptor agonists. Furthermore, it is suitable for use as once-a-day inhalers as independent therapies or combination products with other bronchodilators and/or anti-inflammatory drugs. Finally, β₂-adrenoreceptor modulates the expression of α – synuclein in both directions. And its accumulation is a pathological marker of Parkinson’s disease (PD). PF-610355 is a long-acting inhaled β₂-adrenoreceptor agonist.

PF-610355 is a long-acting inhaled β₂-adrenoreceptor agonist.

How does PF-610355 work on the target? Let’s study it together. In the beginning, PF-610355 is a long-acting (once daily) inhaled β2-adrenoreceptor agonist, with an EC₅₀ of 0.26 nM. In addition, PF-610355 displayed high levels of potency and long DoA on airway smooth muscle. Meanwhile, PF-610355 has the potential for the study of asthma and COPD.

In the second place, PF-610355 has low oral bioavailability due to poor absorption through the gut lumen and high first-pass metabolism and warranted further progression. Nonetheless, PF-610355 has a short half-life (Clint=33 μL/min·mg) that suggested an unbound intrinsic clearance of >10000 mL/min·kg. Interestingly, PF-610355 exhibits an ideal pharmacokinetic profile for an inhaled agent. PF-610355 has encouraging potential to deliver 24 h duration of action in humans with a therapeutic index of at least 10-fold. PF-610355 exhibits very high intrinsic clearance in humans due to glucuronidation. Additionally, PF-610355 reduces the systemic adverse reactions caused by inhalation and swallowing dose after inhalation. There are no significant adverse effects in vitro genotoxicity test and in vivo rat tolerance study.

All in all, PF-610355 is a long-acting inhaled β₂-adrenoreceptor agonist with the potential for the study of asthma and COPD.

References:

Paul A Glossop, et al. J Med Chem. 2010 Sep 23;53(18):6640-52.