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

The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and beta(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 ou...

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Published inJournal of medicinal chemistry Vol. 65; no. 15; pp. 10233 - 10250
Main Authors Carzaniga, Laura, Linney, Ian D., Rizzi, Andrea, Delcanale, Maurizio, Schmidt, Wolfgang, Knight, Christopher K., Pastore, Fiorella, Miglietta, Daniela, Carnini, Chiara, Cesari, Nicola, Riccardi, Benedetta, Mileo, Valentina, Venturi, Luca, Moretti, Elisa, Blackaby, Wesley P., Patacchini, Riccardo, Accetta, Alessandro, Biagetti, Matteo, Bassani, Franco, Tondelli, Marina, Murgo, Annalisa, Battipaglia, Loredana, Villetti, Gino, Puccini, Paola, Catinella, Silvia, Civelli, Maurizio, Rancati, Fabio
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 11.08.2022
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
OBSTRUCTIVE PULMONARY-DISEASE
BITOPIC LIGANDS
PARALLEL-GROUP
DOUBLE-BLIND
TRIPLE THERAPY
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Summary:The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and beta(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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c00609