Discovery, Multiparametric Optimization, and Solid-State Driven Identification of CHF-6550, a Novel Soft Dual Pharmacology Muscarinic Antagonist and β 2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.

Autor:	Carzaniga L; Medicinal Chemistry and Drug Discovery Technologies Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Linney ID; Medicinal Chemistry Department, Charles River, Chesterford Research Park, Saffron Walden, CB10 1XL, Essex United Kingdom., Rizzi A; Medicinal Chemistry and Drug Discovery Technologies Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Schmidt W; Medicinal Chemistry Department, Charles River, Chesterford Research Park, Saffron Walden, CB10 1XL, Essex United Kingdom., Knight CK; Medicinal Chemistry Department, Charles River, Chesterford Research Park, Saffron Walden, CB10 1XL, Essex United Kingdom., Mileo V; Analytics and Early Formulations Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Amadei F; Analytics and Early Formulations Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Pastore F; Pharmacology Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Miglietta D; Pharmacology Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Cesari N; Pharmacokinetics Biochemistry and Metabolism Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Riccardi B; Pharmacokinetics Biochemistry and Metabolism Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Mazzucato R; Medicinal Chemistry and Drug Discovery Technologies Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Ghidini E; Medicinal Chemistry and Drug Discovery Technologies Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Blackaby WP; Medicinal Chemistry Department, Charles River, Chesterford Research Park, Saffron Walden, CB10 1XL, Essex United Kingdom., Patacchini R; AIR Franchise, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Battipaglia L; Safety and Toxicology Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Villetti G; Pharmacology Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Puccini P; Pharmacokinetics Biochemistry and Metabolism Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Catinella S; Analytics and Early Formulations Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Civelli M; Head of Global Research & Preclinical Development, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Rancati F; Medicinal Chemistry and Drug Discovery Technologies Department, Chiesi Farmaceutici S.p.A., Research Center, Largo Belloli 11/a, 43122 Parma, Italy.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jun 27; Vol. 67 (12), pp. 9816-9841. Date of Electronic Publication: 2024 Jun 10.
DOI:	10.1021/acs.jmedchem.4c00298
Abstrakt:	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 β 2 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.
Databáze:	MEDLINE
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