RESUMEN
Spiropiperidines have gained in popularity in drug discovery programmes as medicinal chemists explore new areas of three-dimensional chemical space. This review focuses on the methodology used for the construction of 2-, 3- and 4-spiropiperidines, covering the literature from the last 10 years. It classifies the synthesis of each of the types of spiropiperidine by synthetic strategy: the formation of the spiro-ring on a preformed piperidine ring, and the formation of the piperidine ring on a preformed carbo- or heterocyclic ring. While 3- and 4-spiropiperidines are predominantly synthesised for drug discovery projects, 2-spiropiperidines are synthesised en route to natural products. The lack of 2-spiropiperidines in drug discovery is presumably due to limited general procedures for their synthesis.
RESUMEN
Correction for 'Synthesis of highly substituted 2-spiropiperidines' by Samuel D. Griggs et al., Org. Biomol. Chem., 2018, DOI: 10.1039/c8ob01272e.
RESUMEN
2-Spiropiperidines are a highly desirable, yet under represented structure in drug discovery. 2-Spiropiperidines were synthesised in either a two-pot or one-pot reaction. In the two-pot reaction, the addition of a Weiler dianion to N-Boc imines, followed by deprotection and in situ condensation with a cyclic ketone generated functionalised 2-spiropiperidines in good to excellent yields. In the one-pot reaction, the addition of Chan's diene to N-Boc imines under Maitland-Japp conditions, followed by the addition of sodium bicarbonate and a cyclic ketone formed functionalised 2-spiropiperidines in moderate to good yields.
RESUMEN
A general two-step synthesis of 2-spiropiperidines has been developed. δ-Amino-ß-ketoesters can be reacted with cyclic ketones to generate 2-spiropiperidines in good to excellent yields. The 2-spiropiperidines formed occupy an under-explored region of 3D-chemical space and are novel scaffolds for use in drug discovery programs. These 2-spiropiperidines can be further functionalised to generate small highly sp3 -rich structures, which exhibit an excellent likeness to lead-molecules in drug discovery.
RESUMEN
The lead optimization of a series of potent azaindole IKK2 inhibitors is described. Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Indoles/química , Inhibidores de Proteínas Quinasas/química , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Semivida , Humanos , Quinasa I-kappa B/metabolismo , Indoles/síntesis química , Indoles/farmacocinética , Pulmón/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.