RESUMEN
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
Modification of the potent imidazole-based B-Raf inhibitor SB-590885 resulted in the identification of a series of furan-based derivatives with enhanced CNS penetration. One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Furanos/síntesis química , Furanos/farmacología , Indanos/síntesis química , Indanos/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Animales , Furanos/química , Imidazoles/química , Imidazoles/farmacología , Indanos/química , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Ratas , Accidente Cerebrovascular/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A novel series of pyridone inhibitors has been identified through pharmacophore analysis, as potent antagonists of VLA-4.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Piridonas/síntesis química , Piridonas/farmacología , Sitios de Unión , Diseño de Fármacos , Relación Estructura-Actividad , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
A series of pyridone-N-benzyl-propanoic acids have been optimised to afford potent orally bioavailable VLA-4 antagonists.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Piridonas/farmacología , Administración Oral , Animales , Piridonas/administración & dosificación , Piridonas/farmacocinética , RatasRESUMEN
A novel triarylimidazole derivative, SB-590885 (33), bearing a 2,3-dihydro-1H-inden-1-one oxime substituent has been identified as a potent and extremely selective inhibitor of B-Raf kinase.
Asunto(s)
Imidazoles/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Ciclización , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Proteínas Proto-Oncogénicas B-raf/química , Relación Estructura-ActividadRESUMEN
A series of 6-heteroaryl-pyrazolo[3,4-b]pyridines has been optimised to afford potent inhibitors of Glycogen Synthase Kinase-3 (GSK-3). These analogues display excellent selectivity over the closely related Cyclin Dependent Kinase-2 (CDK-2).
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Piridinas/síntesis química , Animales , Quinasas CDC2-CDC28/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of 6-aryl-pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).