Optimization of M₃ Antagonist–PDE4 Inhibitor (MAPI) Dual Pharmacology Molecules for the Treatment of COPD

Abstract

Aiming at the inhaled treatment of pulmonary diseases, the optimization process of the previously reported MAPI compound 92a is herein described. The project was focused on overcoming the chemical stability issue and achieving a balanced bronchodilator/anti-inflammatory profile in rats in order to be confident in a clinical effect without having to overdose at one of the biological targets. The chemical strategy was based on finetuning of the substitution pattern in the muscarinic and PDE4 structural portions of the dual pharmacology compounds, also making use of the analysis of a proprietary crystal structure in the PDE4 catalytic site. Compound 10f was identified as a chemically stable, potent, and in vivo balanced MAPI lead compound, as assessed in bronchoconstriction and inflammation assays in rats after intratracheal administration. After the in-depth investigation of the pharmacological and solid-state profile, 10f proved to be safe and suitable for development.

Medicinal Polypharmacology in the Clinic – Translating the Polypharmacolome into Therapeutic Benefit

“…However, a subsequent phase II clinical trial has been withdrawn due to “emerging pre-clinical toxicology findings” ( www.clinicaltrials.gov , #NCT04187508); For the treatment of chronic obstructive pulmonary disease (COPD), the Italian company Chiesi Farmaceutici in collaboration with Charles River Laboratories very recently combined antagonism at the M 3 mAChR with inhibition of phosphodiesterase 4 (PDE4) in a so-called MAPI drug candidate (compound 10f; Fig. 2 ) that showed a balanced bronchodilator / anti-inflammatory profile in rats [ 35 ]. The California-based company Theravance Biopharma, on the other hand, published a few years earlier a so-called MABA , i.e.…”

“…For the treatment of chronic obstructive pulmonary disease (COPD), the Italian company Chiesi Farmaceutici in collaboration with Charles River Laboratories very recently combined antagonism at the M 3 mAChR with inhibition of phosphodiesterase 4 (PDE4) in a so-called MAPI drug candidate (compound 10f; Fig. 2 ) that showed a balanced bronchodilator / anti-inflammatory profile in rats [ 35 ].…”