Discovery of a novel class of inhaled dual pharmacology muscarinic antagonist and β2 agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD)

Fabio Rancati; Ian D Linney; Andrea Rizzi; Maurizio Delcanale; Chris K Knight; Wolfgang Schmidt; Fiorella Pastore; Benedetta Riccardi; Valentina Mileo; Chiara Carnini; Nicola Cesari; Wesley P Blackaby; Riccardo Patacchini; Laura Carzaniga

doi:10.1016/j.bmcl.2021.127975

Discovery of a novel class of inhaled dual pharmacology muscarinic antagonist and β₂ agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD)

Bioorg Med Chem Lett. 2021 Jun 1:41:127975. doi: 10.1016/j.bmcl.2021.127975. Epub 2021 Mar 19.

Affiliations

¹ Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
² Medicinal Chemistry Department, Charles River Laboratories, Chesterford Research Park, Saffron Walden, CB10 1XL, Cambridgeshire, United Kingdom.
³ Pharmacology and Toxicology Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
⁴ Pharmacokinetics Biochemistry and Metabolism Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
⁵ Analytics and Early Formulation Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
⁶ Project Leader, Corporate Drug Development, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
⁷ Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy. Electronic address: [email protected].

PMID: 33753262
DOI: 10.1016/j.bmcl.2021.127975

Abstract

The targeting of both the muscarinic and β-adrenergic pathways is a well validated therapeutic approach for the treatment of chronic obstructive pulmonary disease (COPD). In this communication we report our effort to incorporate two pharmacologies into a single chemical entity, whose characteristic must be suitable for a once daily inhaled administration. Contextually, we aimed at a locally acting therapy with limited systemic absorption to minimize side effects. Our lung-tailored design of bifunctional compounds that combine the muscarinic and β-adrenergic pharmacologies by the elaboration of the muscarinic inhibitor 7, successfully led to the potent, pharmacologically balanced muscarinic antagonist and β₂ agonist (MABA) 13.

Keywords: Chronic obstructive pulmonary disease (COPD); Dual pharmacology; Inhaled administration; Muscarinic antagonist; β(2) agonist.

MeSH terms

Administration, Inhalation
Adrenergic beta-2 Receptor Agonists / administration & dosage
Adrenergic beta-2 Receptor Agonists / pharmacology*
Bronchodilator Agents / administration & dosage
Bronchodilator Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Muscarinic Antagonists / administration & dosage
Muscarinic Antagonists / pharmacology*
Pulmonary Disease, Chronic Obstructive / drug therapy*
Pulmonary Disease, Chronic Obstructive / metabolism
Receptor, Muscarinic M3 / antagonists & inhibitors
Receptor, Muscarinic M3 / metabolism
Receptors, Adrenergic, beta-2 / metabolism
Structure-Activity Relationship

Substances

Adrenergic beta-2 Receptor Agonists
Bronchodilator Agents
Muscarinic Antagonists
Receptor, Muscarinic M3
Receptors, Adrenergic, beta-2