1. Academic Validation
  2. Pharmacological preclinical characterization of LAS190792, a novel inhaled bifunctional muscarinic receptor antagonist /β2-adrenoceptor agonist (MABA) molecule

Pharmacological preclinical characterization of LAS190792, a novel inhaled bifunctional muscarinic receptor antagonist /β2-adrenoceptor agonist (MABA) molecule

  • Pulm Pharmacol Ther. 2017 Oct;46:1-10. doi: 10.1016/j.pupt.2017.07.003.
Mònica Aparici 1 Carla Carcasona 2 Israel Ramos 2 José Luís Montero 2 José Luís Ortiz 3 Julio Cortijo 3 Carlos Puig 2 Dolors Vilella 2 Chris Doe 2 Amadeu Gavaldà 2 Montserrat Miralpeix 2
Affiliations

Affiliations

  • 1 Almirall, R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: monica.aparici@almirall.com.
  • 2 Almirall, R&D Center, Sant Feliu de Llobregat, Barcelona, Spain.
  • 3 Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
Abstract

LAS190792 is a novel muscarinic antagonist and β2-adrenoceptor agonist in development for chronic respiratory diseases. This study investigated the pharmacological profile of LAS190792 in comparison to batefenterol, tiotropium, indacaterol and olodaterol. LAS190792 is potent at the human M3 receptor (pIC50: 8.8 in binding assays). It is selective for the β2-adrenoceptor over the β1-and β3-adrenoceptor, and shows a functional potency in a similar range to batefenterol and LABA compounds (pEC50 in spontaneous tone isolated trachea: 9.6). The relaxant potency of LAS190792 in electrically stimulated tissue is similar to batefenterol, with an antimuscarinic activity in presence of propranolol slightly higher than batefenterol (pIC50 of 8.3 versus 7.9 in human tissue). LAS190792 exhibits a sustained duration of action in isolated tissue longer than that of batefenterol. Nebulized LAS190792 inhibits acetylcholine-induced bronchoconstriction in dog with minimal cardiac effects and sustained bronchodilation (t1/2: 13.3 h). In conclusion, these studies suggest that LAS190792 is a dual-acting muscarinic antagonist β2-adrenoceptor agonist that has the potential to be a next generation bronchodilator with long-lasting effects and wide safety margin in humans.

Keywords

Batefenterol ethane disulfonate (PubChem CID 11629376); Bronchodilator; COPD; Long-acting muscarinic antagonist; Long-acting β(2)-adrenoceptor agonist; indacaterol maleate (PubChem CID 6918554); olodaterol free base (PubChem CID 11504295); propranolol hydrochloride (PubChem CID 62882); tiotropium bromide (PubChem CID 5487426).

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