Discovery of CHF-6523, an Inhaled Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.

The design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a topology ensured the desired PI3Kδ selectivity. Achievement of low nanomolar cellular potencies through hinge binder group optimization, reduction of intrinsic permeability through head group optimization to extend lung retention, and screening of crystalline forms suitable for administration as dry powders culminated in the identification of compound .

Comparison of Formoterol, Glycopyrrolate, and Beclomethasone Dipropionate Pharmacokinetic Profile after Inhaled Administration as pMDI Using HFA134a or HFA152a Propellant: Preclinical Assessment of Drug Exposure in Sprague-Dawley Rat Model.

A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate is approved in some geographic areas as pressurized metered dose inhaler (pMDI) formulation for the treatment of asthma and chronic obstructive pulmonary disease. Current pMDIs use hydrofluoroalkanes (HFAs) as a propellant, such as 1,1,1,2-tetrafluoroethane (HFA134a), that have a high global warming potential (GWP), but their use is being progressively lowered to reduce impact on climate. One option to reduce the carbon footprint of the pMDI products while preserving pMDIs as a therapeutic option is reformulating the current pMDIs using low GWP propellants, such as 1,1-difluoroethane (HFA152a).

Discovery, Multiparametric Optimization, and Solid-State Driven Identification of CHF-6550, a Novel Soft Dual Pharmacology Muscarinic Antagonist and β Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.

Clinical guidelines for COPD and asthma recommend inhaled β-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 β 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 .

New insight on porcine carboxylesterases expression and activity in lung tissues.

Over the course of the last twenty years, there has been a growing recognition of the pig's potential as a valuable model for studying human drug metabolism. This study aimed to investigate the expression, enzymatic activity, inhibitory susceptibility, and cellular localization of carboxylesterases (CES) in porcine lung tissue not yet explored. Our results showed that CESs hydrolysis activity followed Michaelis-Menten kinetics in both cytosolic and microsomal fractions of porcine lung tissues (N = 8), with comparable hydrolysis rates for tested substrates, namely 4-nitrophenyl acetate (pNPA), 4-methylumbelliferyl acetate (4-MUA), and fluorescein diacetate (FD).