RESUMEN

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.

Asunto(s)

Agonistas de Receptores Adrenérgicos beta 2 , Antagonistas Muscarínicos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/síntesis química , Antagonistas Muscarínicos/uso terapéutico , Antagonistas Muscarínicos/administración & dosificación , Animales , Humanos , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Administración por Inhalación , Ratas , Descubrimiento de Drogas , Relación Estructura-Actividad , Masculino , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico

RESUMEN

The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and ß2 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.

Asunto(s)

Antagonistas Muscarínicos , Enfermedad Pulmonar Obstructiva Crónica , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Broncodilatadores/uso terapéutico , Descubrimiento de Drogas , Humanos , Pulmón , Antagonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico

RESUMEN

Second-generation synthetic routes to enantiopure sulfone 21 and aldehyde 24 are described. The union of these two intermediates by means of a Julia-Kocienski coupling gave rise to a series of E-configured building blocks that did not prove amenable to transannular cyclization. Alternatively, when the C15-C16 double bond was introduced with Z-geometry by Wittig olefination, spontaneous closure to generate a tetrahydrofuran culminated an ensuing direct dihydroxylation step. The structural assignment to 35, undergirded by detailed 1H and 13C NMR studies, is consistent with proper transannular bonding so as to deliver the entire C1-C26 fragment of PTX2.