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Agonistas similares al GLP-1R Danuglipron y Lotiglipron: una revisión de patentes (2020-2024)

Elena V Tolkacheva¹, Alexandr Yu Saliev¹, Tagir L Salakhov¹

¹Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy ave. 1, Sirius, Krasnodar Region, 354340, Russia.

Current medicinal chemistry

|August 28, 2025

Resumen

Los agonistas orales del péptido tipo glucagón-1 (GLP-1) de próxima generación son prometedores para la diabetes tipo 2 y la obesidad. Las modificaciones estructurales revelan tendencias clave para desarrollar agonistas de GLP-1R de moléculas pequeñas altamente potentes.

Área de la Ciencia:

Química medicinal
Farmacología
Descubrimiento de drogas

Sus antecedentes:

Los agonistas de los receptores de péptido similar al glucagón-1 (GLP-1) han transformado el tratamiento de la diabetes tipo 2 y la obesidad, principalmente a través de terapias inyectables.
Los agonistas de los receptores GLP-1 de molécula pequeña se ofrecen para administración oral, pero carecen de un establecimiento clínico.
El danugliprón y el lotigliprón de Pfizer fueron los primeros agonistas orales de GLP-1R, que sirvieron como prototipos para el desarrollo posterior de medicamentos.

Objetivo del estudio:

Revisar los agonistas de los receptores GLP-1 de la siguiente clase.
Identificar las relaciones estructura-actividad (SAR) de los nuevos agonistas orales del GLP-1R.
Explorar modificaciones químicas para mejorar la potencia y las propiedades del agonista.

Principales métodos:

Análisis de la literatura de patentes desde enero de 2021 hasta julio de 2024.
Busqué en bases de datos como Espacenet y Google Patents agonistas parecidos al danuglipron y al lotiglipron.
Analizado más de 5.000 compuestos de 67 publicaciones de patentes.

Principales resultados:

Se han identificado las principales tendencias SAR para los agonistas orales potentes de la GLP- 1R.
La presencia de un grupo carboxilo mejora la actividad; el reemplazo bioisostérico puede mejorar la EMAD.
Las modificaciones que incluyen fragmentos privilegiados, reemplazos de heterociclos y nuevos derivados de piperidina muestran potencial.
Existe variabilidad en el residuo de alcohol bencílico disubstituido con 2,4-EWG.

Conclusiones:

A pesar de los desafíos iniciales con danugliprón y lotigliprón, la investigación sobre los agonistas orales de GLP-1R está avanzando.
Los nuevos quimiotipos demuestran una alta potencia, lo que sugiere el potencial de futuras terapias aprobadas.
El desarrollo posterior puede superar las complejidades de la señalización del receptor GLP-1 para la administración oral.

Palabras clave:

Diabetes mellitus de tipo 2 El uso de danugliprón Agonistas de los receptores de péptido tipo glucagón El lotigliprón.drogas de la siguiente clase Agonistas orales no peptídicos Agonistas de moléculas pequeñas Relación estructura-actividad

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