2. Academic Validation
  3. Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/ β 2-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile

Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/ β 2-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile

  • J Pharmacol Exp Ther. 2019 Jul;370(1):127-136. doi: 10.1124/jpet.118.255620.
Mònica Aparici 1,  Carla Carcasona 2,  Israel Ramos 2,  José Luís Montero 2,  Raquel Otal 2,  José Luís Ortiz 2,  Julio Cortijo 2,  Carlos Puig 2,  Dolors Vilella 2,  Jorge De Alba 2,  Chris Doe 2,  Amadeu Gavaldà 2,  Montserrat Miralpeix 2
Affiliations

Affiliations

  • 1 Almirall, Research & Development Center, Sant Feliu de Llobregat, Barcelona, Spain (M.A., C.C., I.R., J.L.M., R.O., C.P., D.V., J.D.A., C.D., A.G., M.M.); and Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain (J.L.O., J.C.) [email protected].
  • 2 Almirall, Research & Development Center, Sant Feliu de Llobregat, Barcelona, Spain (M.A., C.C., I.R., J.L.M., R.O., C.P., D.V., J.D.A., C.D., A.G., M.M.); and Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain (J.L.O., J.C.).
PMID: 31085697 DOI: 10.1124/jpet.118.255620
Abstract

AZD8871 is a novel muscarinic antagonist and β 2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M3 receptor (pIC50 in binding assays: 9.5) and shows kinetic selectivity for the M3 (half-life: 4.97 hours) over the M2 receptor (half-life: 0.46 hour). It is selective for the β 2-adrenoceptor over the β 1 and β 3 subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and β 2-adrenoceptor functional activity in isolated guinea pig tissue (pIC50 in electrically stimulated trachea: 8.6; pEC50 in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2- and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchoconstriction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases.

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