RESUMEN
The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.
Asunto(s)
Aminas/química , Factor XIa/antagonistas & inhibidores , Compuestos Macrocíclicos/química , Inhibidores de Serina Proteinasa/síntesis química , Administración Oral , Animales , Sitios de Unión , Diseño de Fármacos , Factor XIa/metabolismo , Semivida , Compuestos Macrocíclicos/metabolismo , Compuestos Macrocíclicos/farmacocinética , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Piridinas/química , Ratas , Inhibidores de Serina Proteinasa/metabolismo , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-ActividadRESUMEN
Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface area and improved the oral bioavailability for the series, albeit at the cost of a decrease in potency.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Factor XIa/antagonistas & inhibidores , Compuestos Macrocíclicos/farmacología , Inhibidores de Serina Proteinasa/farmacología , Amidas/síntesis química , Amidas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Factor XIa/metabolismo , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/química , Relación Estructura-ActividadRESUMEN
The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.8µM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).
Asunto(s)
Anilidas/farmacología , Factor XIa/antagonistas & inhibidores , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Anilidas/síntesis química , Animales , Cristalografía por Rayos X , Perros , Fenilalanina/síntesis química , Conejos , Relación Estructura-ActividadRESUMEN
Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge. A two-pronged strategy, which focused on replacement of the imidazole scaffold and the design of new P1 groups, led to the discovery of potent, orally bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover, pyridine-based macrocycle 19, possessing the phenylimidazole carboxamide P1, exhibited excellent selectivity against relevant blood coagulation enzymes and displayed antithrombotic efficacy in a rabbit thrombosis model.
Asunto(s)
Factor XIa/antagonistas & inhibidores , Fibrinolíticos/síntesis química , Fibrinolíticos/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Animales , Disponibilidad Biológica , Coagulación Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Descubrimiento de Drogas , Fibrinolíticos/farmacocinética , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Modelos Moleculares , Tiempo de Tromboplastina Parcial , Conejos , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad , Trombosis/tratamiento farmacológicoRESUMEN
A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 µM) and excellent selectivity against the relevant blood coagulation enzymes.