Pharmacological Characterization of Abediterol, a Novel Inhaled β₂-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models

Abstract

Abediterol is a novel potent, long-acting inhaled ␤ 2 -adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human ␤ 2 -adrenoceptor and a functional selectivity over ␤ 1 -adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human ␤ 2 -adrenoceptor (E max ϭ 91 Ϯ 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC 50 ϭ 1.9 Ϯ 0.4 nM; t 1 ⁄2 onset ϭ 7-10 min) is not significantly different from that of formoterol, but its duration of action (t 1 ⁄2 ϳ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t 1 ⁄2 ϭ 36 h) than salmeterol (t 1 ⁄2 ϭ 6 h) and formoterol (t 1 ⁄2 ϭ 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile.

Abediterol (LAS100977), a novel long-acting β2-agonist: Efficacy, safety and tolerability in persistent asthma

“…The preclinical evaluation of this agent demonstrated a high potency and selectivity at the b 2 -receptors, with a rapid onset of bronchodilation and long duration of action [4]. A Phase I, first-in-human, single-dose clinical trial, showed a potent bronchodilatory effect of abediterol at doses ranging from 5 mg to 50 mg [5], confirming preclinical data obtained with this compound.…”

Emerging therapeutic strategies in COPD

“…Abediterol (LAS100977; Almirall, Spain) is an inhaled ultra-LABA (long-acting b2 agonist) that has been reported from preclinical studies to be a full b 2 agonist, with an increased affinity and functional sensitivity for b 2 -adrenoceptors over b 1 -adrenoceptors compared with licensed formoterol and indacaterol [8]. LAS100977 was ten-times more potent than salmeterol and similar to formoterol and indacaterol.…”

Lead Generation Approaches Delivering Inhaled β 2 ‐Adrenoreceptor Agonist Drug Candidates

“…Recently, Almirall has disclosed the structure of their clinical candidate (abedi terol) [34], which is structurally different from their previous disclosure, although there have not yet been any medicinal chemistry publication and hence there is no design hypothesis described for the discovery of abediterol herein. They reported on the full pharmacological characterization of abediterol that shows it to be a potent and highly efficacious β 2 AR agonist, with 40-fold selectiv ity against the β 1 AR and a long duration of action.…”