RESUMEN
The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.
Asunto(s)
Compuestos de Anilina/síntesis química , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Amidas/síntesis química , Amidas/farmacología , Compuestos de Anilina/farmacología , Animales , Inhibidores de Cisteína Proteinasa/farmacología , Flúor , Humanos , Cetonas , Relación Estructura-ActividadRESUMEN
6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteasas/química , Piridinas/química , Animales , Sitios de Unión , Catepsinas/metabolismo , Línea Celular , Cristalografía por Rayos X , Humanos , Ratones , Nitrilos/síntesis química , Nitrilos/farmacocinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Relación Estructura-ActividadRESUMEN
A seven-step solid-phase synthesis of spirohydantoins and an eight-step solid-phase synthesis of spiro-2,5-diketopiperazines is reported. Key intermediate in the synthesis of both compound libraries is the resin-bound cyclic alpha,alpha-disubstituted alpha-amino ester, which can be obtained after selective homogeneous reduction of the aliphatic nitro ester using tin(II) chloride dihydrate. Nitro ester, in turn, is synthesized by a high-pressure-assisted [4 + 2] cycloaddition of resin-bound nitro alkene and butadiene, whereas nitro alkene is obtained by a Knoevenagel condensation of resin-bound nitro acetate with an imine. Novel spirohydantoins are obtained by isocyanate coupling with the resin-bound amino ester 5, followed by cyclization cleavage using a base. Novel spiro-2,5-diketopiperazines are obtained by PyBOP coupling of a Fmoc-protected amino acid with resin-bound amino ester, followed by Fmoc deprotection and an acid-assisted cyclization cleavage. After preparation of seven different resin-bound alpha,alpha-disubstituted alpha-amino esters, a 7 x 8 compound library of spirohydantoins was synthesized using eight different isocyanates, and a 7 x 8 compound library of spiro-2,5-diketopiperazines was synthesized using eight different Fmoc amino acids.
Asunto(s)
Técnicas Químicas Combinatorias/métodos , Hidantoínas/síntesis química , Piperazinas/síntesis química , Resinas Sintéticas/química , Compuestos de Espiro/síntesis química , Aminoácidos/química , Cromatografía Liquida , Ciclización , Ésteres/química , Hidantoínas/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Piperazinas/química , Compuestos de Espiro/químicaRESUMEN
In this paper the application of high pressure in multicomponent reactions is discussed. Using high pressure the scope of certain multicomponent reactions can be increased. Reactions are described that can only be performed in a multicomponent fashion when high pressure catalysis is applied. An overview of high pressure catalysed multicomponent reactions is presented with special attention to the domino [4 + 2]/[3 + 2] cycloaddition reaction.