RESUMEN
Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Peroxidasa/antagonistas & inhibidores , Piridinas/farmacología , Triazoles/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Peroxidasa/metabolismo , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f, a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.
Asunto(s)
Factor XIa/antagonistas & inhibidores , Fibrinolíticos/administración & dosificación , Fibrinolíticos/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Factor XIa/química , Factor XIa/metabolismo , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Compuestos Macrocíclicos/administración & dosificación , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Modelos Moleculares , 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
This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.
Asunto(s)
Diseño de Fármacos , Descubrimiento de Drogas , Factor XIa/antagonistas & inhibidores , Compuestos Macrocíclicos/administración & dosificación , Compuestos Macrocíclicos/química , Inhibidores de Serina Proteinasa/administración & dosificación , Inhibidores de Serina Proteinasa/química , Administración Oral , Disponibilidad Biológica , Humanos , Ligandos , Compuestos Macrocíclicos/farmacología , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y1 antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.
Asunto(s)
Antagonistas del Receptor Purinérgico P2Y/farmacología , Urea/análogos & derivados , Animales , Humanos , Espectroscopía de Resonancia Magnética , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Espectrometría de Masa por Ionización de Electrospray , Urea/farmacocinética , Urea/farmacologíaRESUMEN
Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.
Asunto(s)
Compuestos de Fenilurea/química , Inhibidores de Agregación Plaquetaria/química , Antagonistas del Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Tiazoles/química , Urea/análogos & derivados , Administración Oral , Animales , Perros , Semivida , Macaca fascicularis , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Antagonistas del Receptor Purinérgico P2Y/farmacología , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Ratas , Receptores Purinérgicos P2Y1/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Tiazoles/uso terapéutico , Trombosis/tratamiento farmacológico , Urea/farmacocinética , Urea/farmacología , Urea/uso terapéuticoRESUMEN
Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.
Asunto(s)
Fibrinolíticos/química , Compuestos de Fenilurea/química , Antagonistas del Receptor Purinérgico P2Y/química , Piridinas/química , Receptores Purinérgicos P2Y1/química , Urea/química , Animales , Células CACO-2 , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Fibrinolíticos/síntesis química , Fibrinolíticos/farmacocinética , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Tiempo de Tromboplastina Parcial , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Piridinas/farmacocinética , Piridinas/uso terapéutico , Conejos , Ratas , Receptores Purinérgicos P2Y1/metabolismo , Solubilidad , Relación Estructura-Actividad , Trombosis/tratamiento farmacológico , Urea/farmacocinética , Urea/uso terapéutico , Agua/químicaRESUMEN
Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).
Asunto(s)
Inhibidores del Factor Xa , Fibrinolíticos/síntesis química , Imidazoles/síntesis química , Isoxazoles/síntesis química , Pirazoles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Cristalografía por Rayos X , Perros , Fibrinolíticos/química , Fibrinolíticos/farmacología , Humanos , Imidazoles/química , Imidazoles/farmacología , Isoxazoles/química , Isoxazoles/farmacología , Modelos Moleculares , Permeabilidad , Unión Proteica , Pirazoles/química , Pirazoles/farmacología , Conejos , Relación Estructura-Actividad , Trombosis/prevención & controlRESUMEN
As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K(i) of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.
Asunto(s)
Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Benzamidinas/farmacología , Inhibidores del Factor Xa , Guanidinas/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Animales , Anticoagulantes/farmacocinética , Sitios de Unión/efectos de los fármacos , Disponibilidad Biológica , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Enlace de Hidrógeno , Indicadores y Reactivos , Absorción Intestinal , Imitación Molecular , Conejos , Relación Estructura-Actividad , Trombina/químicaRESUMEN
In an effort to identify orally bioavailable factor Xa inhibitors, two isoxazolines libraries were prepared to scan for novel P1 ligands. From this work, 4-chloro-3-aniline was identified as a novel and potent benzamidine mimic.