Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and β<sub>2</sub> Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.
Carzaniga L, Linney ID, Rizzi A, Delcanale M, Schmidt W, Knight CK, Pastore F, Miglietta D, Carnini C, Cesari N, Riccardi B, Mileo V, Venturi L, Moretti E, Blackaby WP, Patacchini R, Accetta A, Biagetti M, Bassani F, Tondelli M, Murgo A, Battipaglia L, Villetti G, Puccini P, Catinella S, Civelli M, Rancati F.
The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and β<sub>2</sub> 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 <b>29</b>, 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 <b>29</b> (CHF-6366) as a clinical candidate, attesting to the successful development of a novel super-soft MABA compound.