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
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
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
Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.
Asunto(s)
Anticoagulantes/química , Anticoagulantes/farmacología , Factor XIa/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Administración Oral , Animales , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Coagulación Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Perros , Factor XIa/metabolismo , Humanos , Modelos Moleculares , Fenilcarbamatos/administración & dosificación , Fenilcarbamatos/química , Fenilcarbamatos/farmacocinética , Fenilcarbamatos/farmacología , Piridinas/administración & dosificación , Piridinas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinéticaRESUMEN
The structure-activity relationships (SAR) of six-membered ring replacements for the imidazole ring scaffold is described. This work led to the discovery of the potent and selective pyridine (S)-23 and pyridinone (±)-24 factor XIa inhibitors. SAR and X-ray crystal structure data highlight the key differences between imidazole and six-membered ring analogs.
Asunto(s)
Factor XIa/antagonistas & inhibidores , Piridinas/farmacología , Piridonas/farmacología , Cristalografía por Rayos X , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Factor XIa/antagonistas & inhibidores , Indazoles/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Factor XIa/efectos de los fármacos , Humanos , Indazoles/administración & dosificación , Indazoles/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa Ki = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.
Asunto(s)
Trombosis de las Arterias Carótidas , Factor XIa , Fibrinolíticos , Pirimidinas , Triazoles , Animales , Ratones , Conejos , Administración Oral , Trombosis de las Arterias Carótidas/tratamiento farmacológico , Factor XIa/antagonistas & inhibidores , Fibrinolíticos/administración & dosificación , Fibrinolíticos/síntesis química , Fibrinolíticos/farmacocinética , Fibrinolíticos/uso terapéutico , Macaca fascicularis , Estructura Molecular , Pirazoles/administración & dosificación , Pirazoles/síntesis química , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Ratas Sprague-Dawley , Relación Estructura-Actividad , Triazoles/administración & dosificación , Triazoles/síntesis química , Triazoles/farmacocinética , Triazoles/uso terapéuticoRESUMEN
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
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
Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model.
Asunto(s)
Antitrombina III , Piperidinas/química , Piridonas/química , Inhibidores de Serina Proteinasa , Trombosis/tratamiento farmacológico , ortoaminobenzoatos/química , Administración Oral , Animales , Antitrombina III/administración & dosificación , Antitrombina III/síntesis química , Antitrombina III/farmacocinética , Derivación Arteriovenosa Quirúrgica , Sitios de Unión , Disponibilidad Biológica , Modelos Animales , Conejos , Inhibidores de Serina Proteinasa/administración & dosificación , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-Actividad , Trombosis/etiologíaRESUMEN
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.
Asunto(s)
Amidas/química , Factor XIa/antagonistas & inhibidores , Compuestos Macrocíclicos/farmacología , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Descubrimiento de Drogas , Enlace de Hidrógeno , Ligandos , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacocinética , Estructura Molecular , Inhibidores de Serina Proteinasa/farmacocinéticaRESUMEN
[reaction: see text]. Metal carbenoid chemistry is used to convert delta-amino beta-ketoesters into 5-substituted 3-oxo prolines, which expands the utility of this class of polyfunctionalized chiral building blocks.
Asunto(s)
Cetoácidos/química , Piperidinas/química , Piperidinas/síntesis química , Prolina/análogos & derivados , Colecistoquinina/antagonistas & inhibidores , Indicadores y Reactivos , EstereoisomerismoRESUMEN
2H-Azirine 2-carboxylate esters (5), the smallest unsaturated nitrogen heterocycle, are readily prepared in enantiomerically pure form via the base-induced elimination of sulfenic acid (RSOH) from nonracemic N-sulfinylaziridine 2-carboxylate esters (4). Optimum yields were obtained when the aziridine was treated with TMSCl at -95 degrees C followed by LDA, which was attributed to the improved leaving group ability of an silicon-oxonium species. By using this new methodology the first asymmetric syntheses of the marine cytotoxic antibiotics (R)-(-)- and (S)-(+)-dysidazirine (2) were accomplished.
RESUMEN
The identification of a new series of selective nonsteroidal progesterone receptor (PR) agonists is reported. Using a high-throughput screening assay based on the measurement of transactivation of a mouse mammary tumor virus promoter-driven luciferase reporter (MMTV-Luc) in human breast cancer T47D cells, a benzimidazole-2-thione analog was identified. Compound 1 showed an apparent EC50 of 53 nM and efficacy of 93% with respect to progesterone. It binds to PR with high affinity (Ki nM), but had no or very low affinity for other steroid hormone receptors. Structure-activity relationship studies of a series of benzimidazole-2-thione analogs revealed critical positions for high PR binding affinity and transactivation potency as well as receptor selectivity, as exemplified by 25. Compound 25 binds to human PR with high affinity (Ki nM) and had at least > 1000-fold selectivity for PR versus other steroid receptors. Molecular modeling studies suggested that these agonists overlap favorably with progesterone in the ligand-binding domain of PR. In T47D cells, compound 25 acted as a full agonist in the MMTV-Luc reporter assay, as well as in the induction of endogenous alkaline phosphatase activity with apparent EC50 values of 4 and 9 nM, respectively. In the immature rat model, compound 25 provided a significant suppression of estrogen-induced endometrium hypertrophy as measured by luminal epithelial height. In contrast, compound 25 was inactive in the luteinizing hormone release assay in young ovariectomized rats. These benzimidazole-2-thione analogs constitute a new series of nonsteroidal PR agonists with an excellent steroid receptor selectivity profile. The differential activities observed in the in vivo progestogenic assays in rat models suggest that these analogs can act as selective PR modulators.
Asunto(s)
Bencimidazoles/farmacología , Imidazoles/farmacología , Receptores de Progesterona/agonistas , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/farmacología , Animales , Bencimidazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/metabolismo , Unión Competitiva/efectos de los fármacos , Línea Celular Tumoral , Femenino , Genes Reporteros , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/metabolismo , Hormona Luteinizante/metabolismo , Acetato de Medroxiprogesterona/metabolismo , Acetato de Medroxiprogesterona/farmacología , Modelos Moleculares , Conformación Molecular , Progesterona/metabolismo , Progesterona/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores de Progesterona/metabolismo , Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/metabolismo , Activación Transcripcional/efectos de los fármacos , Útero/efectos de los fármacos , Útero/metabolismoRESUMEN
Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.