RESUMEN
Cathepsin C plays a key role in the activation of several degradative enzymes linked to tissue destruction in chronic inflammatory and autoimmune diseases. Therefore, Cathepsin C inhibitors could potentially be effective therapeutics for the treatment of diseases such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). In our efforts towards the development of a novel series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C inhibitor 3p, free of aortic binding liability.
Asunto(s)
Aorta/metabolismo , Tratamiento Farmacológico de COVID-19 , Catepsina C/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Acetonitrilos/química , Acetonitrilos/farmacología , Aminoácidos/química , Aminoácidos/farmacología , Compuestos de Bifenilo/farmacología , COVID-19/complicaciones , Humanos , Modelos Moleculares , Estructura Molecular , Síndrome de Dificultad Respiratoria/etiología , Relación Estructura-ActividadRESUMEN
A facile one-pot synthesis of 4-chloro or 4-bromonicotinic acid esters with optional 2- and 2,5-disubstitution on the pyridine ring has been developed from easily accessible enamino keto esters by a formylation followed by in situ intramolecular cyclization strategy under optimized Vilsmeier reaction conditions. The effect of the substituents on the ß-carbon and the nature of the keto functionality were explored in detail to understand the mechanism of pyridine ring formation under the described conditions.