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Discovery, Multiparametric Optimization, and Solid-State Driven Identification of CHF-6550, a Novel Soft Dual Pharmacology Muscarinic Antagonist and ß2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.
Carzaniga, Laura; Linney, Ian D; Rizzi, Andrea; Schmidt, Wolfgang; Knight, Christopher K; Mileo, Valentina; Amadei, Francesco; Pastore, Fiorella; Miglietta, Daniela; Cesari, Nicola; Riccardi, Benedetta; Mazzucato, Roberta; Ghidini, Eleonora; Blackaby, Wesley P; Patacchini, Riccardo; Battipaglia, Loredana; Villetti, Gino; Puccini, Paola; Catinella, Silvia; Civelli, Maurizio; Rancati, Fabio.
Afiliação
  • 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.
J Med Chem ; 67(12): 9816-9841, 2024 Jun 27.
Article em En | MEDLINE | ID: mdl-38857426
ABSTRACT
Clinical guidelines for COPD and asthma recommend inhaled ß-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 ß2 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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Antagonistas Muscarínicos / Agonistas de Receptores Adrenérgicos beta 2 Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Antagonistas Muscarínicos / Agonistas de Receptores Adrenérgicos beta 2 Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article