Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and β 2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.

Autor:	Carzaniga L; Chemistry Research and Drug Design 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; Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Delcanale M; Chemistry Research and Drug Design 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., 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., Carnini C; Project Leader, Corporate Drug Development, 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., Mileo V; Analytics and Early Formulation Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Venturi L; Analytics and Early Formulation Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Moretti E; Analytics and Early Formulation 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; Project Leader, Corporate Drug Development, Chiesi Farmaceutici S.p.A Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Accetta A; Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Biagetti M; Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Bassani F; Pharmacology Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Tondelli M; Pharmacology Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Murgo A; Pharmacology Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy., Battipaglia L; Safety & 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 Formulation 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; Chemistry Research and Drug Design 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] 2022 Aug 11; Vol. 65 (15), pp. 10233-10250. Date of Electronic Publication: 2022 Jul 28.
DOI:	10.1021/acs.jmedchem.2c00609
Abstrakt:	The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and β 2 agonists (MABAs) promises to be an excellent opportunity to reduce formulation issues and boost efficacy through cross-talk and allosteric interactions. Herein, we report the results of our drug discovery campaign aimed at improving the therapeutic index of a previous MABA series by exploiting the super soft-drug concept. The incorporation of a metabolic liability, stable at the site of administration but undergoing rapid systemic metabolism, to generate poorly active and quickly eliminated fragments was pursued. Our SAR studies yielded MABA 29 , which demonstrated a balanced in vivo profile up to 24 h, high instability in plasma and the liver, as well as sustained exposure in the lung. In vitro safety and non-GLP toxicity studies supported the nomination of 29 (CHF-6366) as a clinical candidate, attesting to the successful development of a novel super-soft MABA compound.
Databáze:	MEDLINE
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