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Síntesis de bioisósteros de areno meta sustituidos a partir del propelano

Nils Frank¹, Jeremy Nugent¹, Bethany R Shire¹

¹Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.

|September 15, 2022

Resumen

Los investigadores desarrollaron biciclo[3.1.1]heptanos (BCHeps) como nuevos bioisósteros de metaareno para el diseño de fármacos. Estos motivos ricos en sp3 ofrecen una mejor estabilidad metabólica y solubilidad en comparación con los anillos de benceno tradicionales.

Área de la Ciencia:

Química medicinal
Síntesis orgánica
Descubrimiento de drogas

Sus antecedentes:

Los hidrocarburos de jaula de anillo pequeño sirven como bioisósteros valiosos para los anillos de benceno sustituidos en el diseño de fármacos.
Las estructuras de jaula existentes como el biciclo[1.1.1]pentano ofrecen propiedades farmacocinéticas mejoradas pero carecen de análogos de metaareno.
La síntesis de isósteros saturados para arenas meta sustituidas es un desafío debido a las dificultades para reproducir vectores sustituyentes.

Objetivo del estudio:

Desarrollar nuevos biciclo [3.1.1] heptanos (BCHeps) como bioisósteros para anillos de benceno meta sustituidos.
Establecer vías sintéticas convenientes para el BCHeps a partir del propeleno [3.1.1].
Evaluar las propiedades similares al fármaco y la estabilidad metabólica de los análogos que contienen BCHeps.

Principales métodos:

Síntesis en escala multigramática del propeleno [3.1.1].
Transformaciones basadas en radicales de [3.1.1]propelano para generar BCHeps sustituidos.
Síntesis de análogos farmacéuticos que incorporan BCHeps.
Comparación de las propiedades de absorción, distribución, metabolismo y excreción (ADME).

Principales resultados:

Acceso cómodo a los biciclo[3.1.1]heptanos (BCHeps) desde el propeleno [3.1.1].
Síntesis exitosa de BCHeps medicamente relevantes sustituidos por átomos de carbono y heteroatomo.
Los análogos de BCHeps muestran una mayor estabilidad metabólica en comparación con los fármacos primarios que contienen areno.
Potencial demostrado de BCHeps como motivos ricos en sp3 para el diseño de fármacos.

Conclusiones:

Los BCHeps proporcionan un sustituto sintético viable para los anillos de benceno meta-sustituidos.
Los métodos desarrollados permiten la preparación de BCHeps en escalas útiles.
Los BCHeps representan un andamio prometedor para mejorar las propiedades farmacocinéticas en los programas de descubrimiento de fármacos.

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