%0 Journal Article
%T Discovery, Multiparametric Optimization, and Solid-State Driven Identification of CHF-6550, a Novel Soft Dual Pharmacology Muscarinic Antagonist and β2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.
%A Carzaniga L
%A Linney ID
%A Rizzi A
%A Schmidt W
%A Knight CK
%A Mileo V
%A Amadei F
%A Pastore F
%A Miglietta D
%A Cesari N
%A Riccardi B
%A Mazzucato R
%A Ghidini E
%A Blackaby WP
%A Patacchini R
%A Battipaglia L
%A Villetti G
%A Puccini P
%A Catinella S
%A Civelli M
%A Rancati F
%J J Med Chem
%V 67
%N 12
%D 2024 Jun 27
%M 38857426
%F 8.039
%R 10.1021/acs.jmedchem.4c00298
%X Clinical guidelines for COPD and asthma recommend inhaled β-adrenergic agonists, muscarinic antagonists, and, for frequent exacerbators, inhaled corticosteroids, with the challenge of combining them into a single device. The MABA (muscarinic antagonist and β2 agonist) concept has the potential to simplify this complexity while increasing the efficacy of both pharmacologies. In this article, we report the outcome of our solid-state driven back-up program that led to the discovery of the MABA compound CHF-6550. A soft drug approach was applied, aiming at high plasma protein binding and high hepatic clearance, concurrently with an early stage assessment of crystallinity through a dedicated experimental workflow. A new chemotype was identified, the diphenyl hydroxyacetic esters, able to generate crystalline material. Among this class, CHF-6550 demonstrated in vivo efficacy, suitability for dry powder inhaler development, favorable pharmacokinetics, and safety in preclinical settings and was selected as a back-up candidate, fulfilling the desired pharmacological and solid-state profile.