2. Academic Validation
  3. Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and β2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases

Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and β2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases

  • J Med Chem. 2022 Aug 11;65(15):10233-10250. doi: 10.1021/acs.jmedchem.2c00609.
Laura Carzaniga 1,  Ian D Linney 2,  Andrea Rizzi 1,  Maurizio Delcanale 1,  Wolfgang Schmidt 2,  Christopher K Knight 2,  Fiorella Pastore 3,  Daniela Miglietta 3,  Chiara Carnini 4,  Nicola Cesari 5,  Benedetta Riccardi 5,  Valentina Mileo 6,  Luca Venturi 6,  Elisa Moretti 6,  Wesley P Blackaby 2,  Riccardo Patacchini 4,  Alessandro Accetta 1,  Matteo Biagetti 1,  Franco Bassani 3,  Marina Tondelli 3,  Annalisa Murgo 3,  Loredana Battipaglia 7,  Gino Villetti 3,  Paola Puccini 5,  Silvia Catinella 6,  Maurizio Civelli 8,  Fabio Rancati 1
Affiliations

Affiliations

  • 1 Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy.
  • 2 Medicinal Chemistry Department, Charles River, Chesterford Research Park, Saffron Walden, CB10 1XL Essex, United Kingdom.
  • 3 Pharmacology Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy.
  • 4 Project Leader, Corporate Drug Development, Chiesi Farmaceutici S.p.A Research Center, Largo Belloli 11/a, 43122 Parma, Italy.
  • 5 Pharmacokinetics Biochemistry and Metabolism Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy.
  • 6 Analytics and Early Formulation Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy.
  • 7 Safety & Toxicology Department, Chiesi Farmaceutici S.p.A Research Center, Largo Belloli 11/a, 43122 Parma, Italy.
  • 8 Head of Global Research & Preclinical Development, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy.
PMID: 35901125 DOI: 10.1021/acs.jmedchem.2c00609
Abstract

The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and β2 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.

Figures
Products