Pharmacologic Characterization of GSK-961081 (TD-5959), a First-in-Class Inhaled Bifunctional Bronchodilator Possessing Muscarinic Receptor Antagonist and β₂-Adrenoceptor Agonist Properties

Abstract

The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [TD-5959; (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin-4-yl [1,19-biphenyl]-2-ylcarbamate], a novel first-in-class inhaled bifunctional compound possessing both muscarinic antagonist (MA) and b 2 -adrenoceptor agonist (BA) properties (MABA). In competition radioligand binding studies at human recombinant receptors, GSK-961081 displayed high affinity for hM 2 (K i 5 1.4 nM), hM 3 muscarinic receptors (K i 5 1.3 nM) and hb 2 -adrenoceptors (K i 5 3.7 nM). GSK-961081 behaved as a potent hb 2 -adrenoceptor agonist (EC 50 5 0.29 nM for stimulation of cAMP levels) with 440-and 320-fold functional selectivity over hb 1 -and hb 3 -adrenoceptors, respectively. In guinea pig isolated tracheal tissues, GSK-961081 produced smooth muscle relaxation through MA (EC 50 5 50.2 nM), BA (EC 50 524.6 nM), and MABA (EC 50 5 11 nM) mechanisms. In the guinea pig bronchoprotection assay, inhaled GSK-961081 produced potent, dose-dependent inhibition of bronchoconstrictor responses via MA (ED 50 5 33.9 mg/ml), BA (ED 50 5 14.1 mg/ml), and MABA (ED 50 5 6.4 mg/ml) mechanisms. Significant bronchoprotective effects of GSK-961081 were evident in guinea pigs via MA, BA, and MABA mechanisms for up to 7 days after dosing. The lung selectivity index of GSK-961081 in guinea pigs was 55-to 110-fold greater than that of tiotropium with respect to systemic antimuscarinic antisialagogue effects and was 10-fold greater than that of salmeterol with respect to systemic b 2 -adrenoceptor hypotensive effects. These preclinical findings studies suggest that GSK-961081 has the potential to be a promising next-generation inhaled lung-selective bronchodilator for the treatment of airway diseases, including chronic obstructive pulmonary disease.

Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/β2-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile

“…This was confirmed in human bronchi, where propranolol only produced a decrease in the potency of AZD8871 of 2-fold, whereas batefenterol showed a significant shift in potency of 6-fold. Our results are in agreement with published data, in which batefenterol showed about 5-fold higher potency for the b 2 -adrenoceptor than for the muscarinic receptors in in vitro studies (Hegde et al, 2014) and a noteworthy reduction in the bronchodilator effect under propranolol blockade in clinical trials (Norris and Ambery, 2014). The profile of LAS190792, a MABA compound that also reached clinical stages, is not very different from that of batefenterol, with a drop in potency in human bronchi under propranolol blockade of 5-fold (Aparici et al, 2017).…”

“…than tiotropium (Salmon et al, 2013). In contrast, batefenterol dissociates very fast from the M 3 receptor, with a residence time of 0.16 6 0.02 hour, in agreement with previous publications (Hegde et al, 2014). Other MABAs such as LAS190792 have also exhibited a short residence time at the M 3 receptor (0.2 6 0.1 hour, data not shown).…”

“…These data suggest that, unlike batefenterol and LAS190792, binding kinetics is probably one of the mechanisms responsible for the duration of action of AZD8871. Some authors have suggested that the residence time at the receptor may be involved in the duration of action of b 2 -adrenoceptor agonists (Casarosa et al, 2011), but no clear relationship between receptor dissociation kinetics and functional effects has been demonstrated (Hegde et al, 2014;Ramos et al, 2018). Another factor that may contribute to the long duration of action of AZD8871 is the character of the two basic centers in its structure.…”

Pharmacology of novel treatments for COPD: are fixed dose combination LABA/LAMA synergistic?

“…Such a long duration is likely due to retention of the drug within the lung environment. This is reflected in a 2–3 fold order of magnitude difference in selectivity for the airways over extra-pulmonary sites containing muscarinic and β 2 -adrenoceptors ( 80 ). One characteristic not been reported for GSK961081, but is a feature of this drug class, is the simultaneous binding to orthosteric and allosteric sites of the muscarinic and β 2 -adrenoceptor.…”

Pharmacokinetics, Excretion, and Mass Balance of [14C]‐Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men

“…Batefenterol (GSK961081), a novel bifunctional molecule combining muscarinic acetylcholine receptor antagonism (M2 and M3) and β 2 ‐adrenoreceptor agonism, is in development for the treatment of COPD . This bifunctional molecule has advantages over the use of 2 separate compounds.…”