Inhalation by Design: Novel Ultra-Long-Acting β₂-Adrenoreceptor Agonists for Inhaled Once-Daily Treatment of Asthma and Chronic Obstructive Pulmonary Disease That Utilize a Sulfonamide Agonist Headgroup

Abstract

A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.

Pharmacology and Therapeutics of Bronchodilators

“…PF-610355. PF-610355 is a member of a novel series of potent and selective sulfonamide-derived ␤ 2 -AR agonists (Glossop et al, 2010). The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state.…”

Progress and Prospects for Long-Acting Β 2 -Agonists in the Treatment of Chronic Obstructive Pulmonary Disease

“…PF-610355 -представитель серии сильных и селективных сульфонамидных производных агонис-тов β 2 -адренорецепторов [52]. У здоровых людей продолжительность действия 450 мкг PF-610355 на дыхательные пути, которое оценивали посред-ством плетизмографии, было больше, чем 50 мкг сальметерола к 9,44 ч, что указывало на потенциал устойчивого фармакологического влияния на легкие [53].…”

Progress and Prospects for Long-Acting Β 2 -Agonists in the Treatment of Chronic Obstructive Pulmonary Disease (Copd)

“…PF-610355 is a member of a series of potent and selective sulfonamide derived β 2 -adrenoceptor agonists [52]. In healthy subjects, duration of action of PF-610355 450 µg on airways determined by plethysmography was superior to salmeterol 50 µg by 9.77 h indicating the potential for sustained pharmacological effect in the lung [53].…”

“…Also in 70 COPD patients who were GOLD stage 2/3, all doses of abediterol (0.625-10 μg) provided clinically and statistically significant, dose-dependent improvements in bronchodilation versus placebo, and were well tolerated [51]. Interestingly abediterol 2.5, 5 and 10 μg gave significant improvements versus indacaterol.PF-610355 is a member of a series of potent and selective sulfonamide derived β 2 -adrenoceptor agonists [52]. In healthy subjects, duration of action of PF-610355 450 µg on airways determined by plethysmography was superior to salmeterol 50 µg by 9.77 h indicating the potential for sustained pharmacological effect in the lung [53].…”