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Estudios de relación estructura-actividad hacia la optimización de agonistas de moléculas pequeñas selectivas de

Kenneth J Wilson¹, Maria Esteban-Lopez², Courtney Myhr²

¹National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

Journal of medicinal chemistry

|February 19, 2026

Resumen

Los investigadores identificaron una nueva molécula pequeña, el compuesto 68, como el primer agonista completo del receptor de péptidos de la familia Relaxina/Insulin-like 2 (RXFP2). Este potente compuesto muestra una gran promesa para el estudio de la activación de RXFP2 en diversos sistemas fisiológicos.

Área de la Ciencia:

Farmacología
Endocrinología
Química Medicinal

Sus antecedentes:

El receptor de péptidos de la familia Relaxina/Insulin-like 2 (RXFP2) desempeña un papel en diversos procesos fisiológicos.
La identificación de agonistas específicos para RXFP2 es crucial para el desarrollo terapéutico y la investigación.
Los moduladores de molécula pequeña existentes para RXFP2 son limitados.

Objetivo del estudio:

Descubrir y optimizar agonistas de moléculas pequeñas dirigidos al receptor humano RXFP2.
Identificar un agonista RXFP2 potente y eficaz con propiedades farmacológicas favorables.
Desarrollar un candidato preclínico para investigar la función de RXFP2 en la remodelación ósea y otros sistemas.

Principales métodos:

Cribado de alto rendimiento de 147.334 moléculas pequeñas contra células HEK293T-RXFP2.
Extensos estudios de relación estructura-actividad (SAR) para optimizar los compuestos líderes.
Evaluaciones farmacocinéticas y de potencia in vitro e in vivo.

Principales resultados:

Se identificó el compuesto 5 como un agonista modesto inicial de la Insulin-Like3 (INSL3).
El compuesto 68 emergió como el primer agonista completo de molécula pequeña de RXFP2.
El compuesto 68 demostró una potencia nanomolar y una farmacocinética in vivo favorable con alta exposición sistémica.

Conclusiones:

El compuesto 68 es un agonista completo de molécula pequeña de RXFP2 potente y de primera clase.
El compuesto 68 exhibe características preclínicas prometedoras para una mayor investigación.
Este descubrimiento proporciona una herramienta valiosa para explorar el papel de RXFP2 en la remodelación ósea y la fisiología.

Palabras clave:

agonista de molécula pequeña RXFP2 agonista completo relación estructura-actividad farmacología endocrinología química medicinal

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