RESUMEN
We report the identification of a novel biaryl template for H(+)/K(+) ATPase inhibition. Evaluation of critical SAR features within the biaryl imidazole framework and the use of pharmacophore modelling against known imidazopyridine and azaindole templates suggested that the geometry of the molecule is key to achieving activity. Herein we present our work optimising the potency of the molecule through modifications and substitutions to each of the ring systems. In particular sub-micromolar potency is achieved with (4b) presumably through a proposed intramolecular hydrogen bond that ensures the required imidazole basic centre is appropriately located.
Asunto(s)
Descubrimiento de Drogas/métodos , Imidazoles/química , Inhibidores de la Bomba de Protones , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Imidazoles/metabolismo , Imidazoles/farmacología , Relación Estructura-ActividadRESUMEN
A variety of basic, heterocyclic templates has been reported as potassium-competitive, acid pump antagonists. Herein, we report a comparison of potencies of these templates and others to establish which offers the best start point for further systematic optimisation. Modifications were carried out to improve the developability profile of the more potent 1H-pyrrolo[2,3-c]pyridine template, affording molecules with improved overall in vitro characteristics versus the reported clinical candidate AR-H047108, and comparable to the clinically efficacious AZD-0865.
Asunto(s)
Compuestos Heterocíclicos/farmacología , Inhibidores de la Bomba de Protones , Piridinas/farmacología , Unión Competitiva , Diseño de Fármacos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in animal models of gastric acid secretion following oral administration, as well as a good overall developability profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6 position and optimization of developability characteristics through modulation of global physico-chemical properties.
Asunto(s)
Inhibidores de la Bomba de Protones , Inhibidores de la Bomba de Protones/química , Piridinas/química , Administración Oral , Animales , Perros , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Inhibidores de la Bomba de Protones/síntesis química , Inhibidores de la Bomba de Protones/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.