RESUMO
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.
Assuntos
Desenho de Fármacos , Descoberta de Drogas , Fator XIa/antagonistas & inibidores , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/química , Inibidores de Serina Proteinase/administração & dosagem , Inibidores de Serina Proteinase/química , Administração Oral , Disponibilidade Biológica , Humanos , Ligantes , Compostos Macrocíclicos/farmacologia , Modelos Moleculares , Estrutura Molecular , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Anilidas/farmacologia , Fator XIa/antagonistas & inibidores , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Anilidas/síntese química , Animais , Cristalografia por Raios X , Cães , Fenilalanina/síntese química , Coelhos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Fator XIa/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Administração Oral , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Coagulação Sanguínea/efeitos dos fármacos , Cristalografia por Raios X , Cães , Fator XIa/metabolismo , Humanos , Modelos Moleculares , Fenilcarbamatos/administração & dosagem , Fenilcarbamatos/química , Fenilcarbamatos/farmacocinética , Fenilcarbamatos/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinéticaRESUMO
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.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Fator XIa/antagonistas & inibidores , Indazóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Fator XIa/efeitos dos fármacos , Humanos , Indazóis/administração & dosagem , Indazóis/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
In an effort to identify a potential back-up to apixaban (Eliquis®), we explored a series of diversified P4 moieties. Several analogs with substituted gem-dimethyl moieties replacing the terminal lactam of apixaban were identified which demonstrated potent FXa binding affinity (FXa Ki), good human plasma anticoagulant activity (PT EC2x), cell permeability, and oral bioavailability.
Assuntos
Inibidores do Fator Xa/farmacologia , Fator Xa/metabolismo , Pirazóis/farmacologia , Piridonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/química , Humanos , Estrutura Molecular , Pirazóis/administração & dosagem , Pirazóis/química , Piridonas/administração & dosagem , Piridonas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Trombose das Artérias Carótidas , Fator XIa , Fibrinolíticos , Pirimidinas , Triazóis , Animais , Camundongos , Coelhos , Administração Oral , Trombose das Artérias Carótidas/tratamento farmacológico , Fator XIa/antagonistas & inibidores , Fibrinolíticos/administração & dosagem , Fibrinolíticos/síntese química , Fibrinolíticos/farmacocinética , Fibrinolíticos/uso terapêutico , Macaca fascicularis , Estrutura Molecular , Pirazóis/administração & dosagem , Pirazóis/síntese química , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/síntese química , Triazóis/farmacocinética , Triazóis/uso terapêuticoRESUMO
Apixaban (BMS-562247; 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide), a direct inhibitor of activated factor X (FXa), is in development for the prevention and treatment of various thromboembolic diseases. With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases. It produces a rapid onset of inhibition of FXa with association rate constant of 20 µM⻹/s approximately and inhibits free as well as prothrombinase- and clot-bound FXa activity in vitro. Apixaban also inhibits FXa from rabbits, rats and dogs, an activity which parallels its antithrombotic potency in these species. Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation. Pre-clinical studies of apixaban in animal models have demonstrated dose-dependent antithrombotic efficacy at doses that preserved hemostasis. Apixaban improves pre-clinical antithrombotic activity, without excessive increases in bleeding times, when added on top of aspirin or aspirin plus clopidogrel at their clinically relevant doses. Apixaban has good bioavailability, low clearance and a small volume of distribution in animals and humans, and a low potential for drug-drug interactions. Elimination pathways for apixaban include renal excretion, metabolism and biliary/intestinal excretion. Although a sulfate conjugate of Ο-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa. Together, these non-clinical findings have established the favorable pharmacological profile of apixaban, and support the potential use of apixaban in the clinic for the prevention and treatment of various thromboembolic diseases.
Assuntos
Descoberta de Drogas/história , Inibidores Enzimáticos , Inibidores do Fator Xa , Fibrinolíticos , Pirazóis , Piridonas , Animais , Avaliação Pré-Clínica de Medicamentos/história , Inibidores Enzimáticos/química , Inibidores Enzimáticos/história , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Fibrinolíticos/química , Fibrinolíticos/história , Fibrinolíticos/farmacocinética , Fibrinolíticos/uso terapêutico , História do Século XX , Humanos , Pirazóis/química , Pirazóis/história , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Piridonas/química , Piridonas/história , Piridonas/farmacocinética , Piridonas/uso terapêutico , Tromboembolia/tratamento farmacológicoRESUMO
Apixaban is a potent, direct, selective, and orally active inhibitor of coagulation factor Xa. Rate constants for apixaban binding to free and prothrombinase-bound factor Xa were measured using multiple techniques. The inhibition mechanism was determined in purified systems and in a plasma prothrombin clotting time assay. Apixaban inhibits factor Xa with a K(i) of 0.25 nM at 37°C, an association rate constant of approximately 20 µM(-1) s(-1), and a dissociation half-life of 1-2 min. Under physiological conditions apixaban exhibits mixed-type inhibition and maintains high factor Xa affinity with a K(i) of 0.62 nM and association rate constant of 12 µM(-1) s(-1) for prothrombinase, and a K(i) of 1.7 nM and association rate constant of 4 µM(-1) s(-1) for the prothrombinase:prothrombin complex. Experiments in prothrombin depleted human plasma showed that the mechanism and kinetics of inhibition are maintained in plasma. The mechanistic detail derived from these experiments can be used to understand and interpret the pharmacodynamic action of apixaban.
Assuntos
Inibidores do Fator Xa , Pirazóis/farmacologia , Piridonas/farmacologia , Fator Xa/metabolismo , Humanos , Cinética , Pirazóis/sangue , Pirazóis/química , Piridonas/sangue , Piridonas/química , Relação Estrutura-Atividade , Termodinâmica , Tromboplastina/antagonistas & inibidores , Tromboplastina/metabolismoRESUMO
Apixaban is a potent, highly selective, reversible, oral, direct factor Xa (fXa) inhibitor in development for thrombosis prevention and treatment. The preclinical pharmacokinetic (PK) attributes of apixaban feature small volume of distribution (Vd), low systemic clearance (CL), and good oral bioavailability. Apixaban is well absorbed in rat, dog, and chimpanzee, with absolute oral bioavailability of approximately 50% or greater. The steady-state Vd of apixaban is approximately 0.5, 0.2, and 0.17 l/kg in rats, dogs, and chimpanzees, while CL is approximately 0.9, 0.04, and 0.018 l/h/kg, respectively. In vitro metabolic clearance of apixaban is also low. Renal clearance comprises approximately 10-30% of systemic clearance in rat, dog, and chimpanzee. Anti-fXa activity, prothrombin time (PT), and HEPTEST(®) clotting time (HCT) prolongation correlated well with plasma apixaban concentration in rat, dog and chimpanzee. There was no lag time between apixaban plasma concentration and the pharmacodynamic (PD) markers, suggesting a rapid onset of action of apixaban. The PK/PD analyses were performed using an inhibitory E (max) model for anti-fXa assay and a linear model for PT and HCT assays. The IC(50) values for anti-fXa activity were 0.73 ± 0.03 and 1.5 ± 0.15 µM for rat and dog, respectively. The apparent K ( i ) values for PT were approximately 1.7, 6.6, and 4.8 µM for rat, dog and chimpanzee, respectively. The apparent K ( i ) for HCT was approximately 1.3 µM for dog. Apixaban exhibits desirable PK and PD properties for clinical development with good oral bioavailability, small Vd, low CL, and direct, predictable, concentration-dependent PD responses.
Assuntos
Anticoagulantes/farmacocinética , Inibidores do Fator Xa , Pirazóis/farmacocinética , Piridonas/farmacocinética , Animais , Proteínas Sanguíneas/metabolismo , Cães , Humanos , Taxa de Depuração Metabólica , Pan troglodytes , Ligação Proteica , Pirazóis/farmacologia , Piridonas/farmacologia , Ratos , Especificidade da Espécie , Tempo de Coagulação do Sangue TotalRESUMO
We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate.
Assuntos
Anticoagulantes/síntese química , Desenho de Fármacos , Inibidores do Fator Xa , Isoxazóis/síntese química , Pirazóis/síntese química , Piridonas/síntese química , Sulfonas/síntese química , Anticoagulantes/química , Anticoagulantes/farmacologia , Cristalografia por Raios X , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Piridonas/química , Piridonas/farmacologia , Sulfonas/química , Sulfonas/farmacologiaRESUMO
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.
Assuntos
Fator XIa/antagonistas & inibidores , Fibrinolíticos/síntese química , Fibrinolíticos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Animais , Disponibilidade Biológica , Coagulação Sanguínea/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Descoberta de Drogas , Fibrinolíticos/farmacocinética , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Modelos Moleculares , Tempo de Tromboplastina Parcial , Coelhos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Trombose/tratamento farmacológicoRESUMO
Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa) inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido linker between the pyrazole and proximal phenyl moiety of the razaxaban scaffold was replaced with a methylene group. The resulting ketones demonstrated excellent potency and selectivity for fXa but initially had poor oral bioavailability. Optimization by conversion from a P1 aminobenzisoxazole to a P1 p-methoxyphenyl residue, replacing the 3-trifluoromethylpyrazole with a 3-amidopyrazole, and employing a pyridone P4 group provided a fXa inhibitor with a potency and pharmacokinetic profile equivalent to that of razaxaban and improved selectivity over thrombin.
Assuntos
Inibidores do Fator Xa , Pirazóis/química , Pirazóis/farmacologia , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Animais , Células CACO-2 , Cães , Humanos , Pirazóis/farmacocinética , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antitrombina III , Piperidinas/química , Piridonas/química , Inibidores de Serina Proteinase , Trombose/tratamento farmacológico , ortoaminobenzoatos/química , Administração Oral , Animais , Antitrombina III/administração & dosagem , Antitrombina III/síntese química , Antitrombina III/farmacocinética , Derivação Arteriovenosa Cirúrgica , Sítios de Ligação , Disponibilidade Biológica , Modelos Animais , Coelhos , Inibidores de Serina Proteinase/administração & dosagem , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-Atividade , Trombose/etiologiaRESUMO
With the introduction of thrombin and factor Xa inhibitors to the oral anticoagulant market, significant improvements in both efficacy and safety have been achieved. Early clinical and preclinical data suggest that inhibitors of factor XIa can provide a still safer alternative, with expanded efficacy for arterial indications. This Perspective provides an overview of target rationale and details of the discovery and development of inhibitors of factor XIa as next generation antithrombotic agents.
Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Fator XIa/antagonistas & inibidores , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Domínio Catalítico , Ensaios Clínicos como Assunto , Fator XIa/química , Fator XIa/metabolismo , Humanos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P1 moieties that resulted in the identification of the p-methoxyphenyl P1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.
Assuntos
Inibidores do Fator Xa , Fibrinolíticos/síntese química , Pirazóis/síntese química , Piridonas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Coagulação Sanguínea/efeitos dos fármacos , Cristalografia por Raios X , Cães , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacologia , Humanos , Técnicas In Vitro , Modelos Moleculares , Estrutura Molecular , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Coelhos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/química , Fator XIa/antagonistas & inibidores , Compostos Macrocíclicos/farmacologia , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Descoberta de Drogas , Ligação de Hidrogênio , Ligantes , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Estrutura Molecular , Inibidores de Serina Proteinase/farmacocinéticaRESUMO
Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.
Assuntos
Anticoagulantes/química , Anticoagulantes/uso terapêutico , Fator XIa/antagonistas & inibidores , Isoquinolinas/química , Isoquinolinas/uso terapêutico , Trombose/tratamento farmacológico , para-Aminobenzoatos/química , para-Aminobenzoatos/uso terapêutico , Animais , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Cristalografia por Raios X , Cães , Descoberta de Drogas , Fator XIa/química , Fator XIa/metabolismo , Humanos , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Masculino , Simulação de Acoplamento Molecular , Coelhos , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Trombose/sangue , para-Aminobenzoatos/farmacocinética , para-Aminobenzoatos/farmacologiaRESUMO
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).
Assuntos
Inibidores do Fator Xa , Fibrinolíticos/síntese química , Imidazóis/síntese química , Isoxazóis/síntese química , Pirazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Cristalografia por Raios X , Cães , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Modelos Moleculares , Permeabilidade , Ligação Proteica , Pirazóis/química , Pirazóis/farmacologia , Coelhos , Relação Estrutura-Atividade , Trombose/prevenção & controleRESUMO
Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor.
Assuntos
Inibidores do Fator Xa , Pirazóis/síntese química , Administração Oral , Animais , Derivação Arteriovenosa Cirúrgica , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Fator Xa/química , Humanos , Pirazóis/farmacocinética , Pirazóis/farmacologia , Coelhos , Relação Estrutura-Atividade , Trombose/prevenção & controleRESUMO
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.