RESUMEN
Initial evaluation of a series 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines revealed a C(1') carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1') carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine template.
Asunto(s)
Ácidos/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Pirroles/químicaRESUMEN
Exploration of the SAR around a series of 3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines led to the discovery of novel pyrrolopyridine inhibitors of the IGF-1R tyrosine kinase. Several compounds demonstrated nanomolar potency in enzyme and cellular mechanistic assays.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Piridinas/química , Pirroles/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptor IGF Tipo 1/metabolismo , Relación Estructura-ActividadRESUMEN
The evaluation of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines as inhibitors of the IGF-1R (IGF-IR) receptor tyrosine kinase is reported. Examples demonstrate nanomolar potencies in in vitro enzyme and mechanistic cellular assays as well as promising in vivo pharmacokinetics in rat.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Descubrimiento de Drogas , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/química , RatasRESUMEN
The SAR of C5' functional groups with terminal basic amines at the C6 aniline of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines is reported. Examples demonstrate potent inhibition of IGF-1R with 1000-fold selectivity over JNK1 and 3 in enzymatic assays.
Asunto(s)
MAP Quinasa Quinasa 4/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Modelos Moleculares , Pirimidinas/química , Pirroles/química , Relación Estructura-ActividadRESUMEN
The optimization of imidazo[1,2-a]pyridine inhibitors as potent and selective inhibitors of IGF-1R is presented. Further optimization of oral exposure in mice is also discussed. Detailed selectivity, in vitro activity, and in vivo PK profiles of an optimized compound is also highlighted.
Asunto(s)
Química Farmacéutica/métodos , Piridinas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/química , Administración Oral , Compuestos de Anilina/química , Animales , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Conformación Molecular , Piridinas/síntesis química , Piridinas/farmacología , Receptor de Insulina/metabolismoRESUMEN
A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
Asunto(s)
Antineoplásicos/química , Receptores ErbB/antagonistas & inhibidores , Pirimidinas/farmacología , Pirrolidinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Administración Oral , Animales , Ratones , Farmacocinética , Pirimidinas/síntesis química , Pirrolidinas/síntesis química , Relación Estructura-ActividadRESUMEN
A synthetic route to bisanilino-1H-pyrrolo[2,3-d]pyrimidines has been discovered, wherein the C(6)-chloride reactivity is necessarily enhanced via reversible acid-catalyzed internal activation of the pyrimidine ring by a C(1')-carboxamide moiety. Subsequent selective nucleophilic displacements at C(6) and C(1') constitute a one-pot tandem protocol for the rapid assembly of bisanilino-1H-pyrrolo[2,3-d]pyrimidines.