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1.
Leuk Res ; 88: 106286, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31865062

RESUMEN

Diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell non-Hodgkin lymphoma (NHL), is categorized into two major subtypes, activated B-cell-like (ABC) and germinal center B-cell-like (GCB). The ABC subtype is associated with worse prognosis than the GCB subtype using currently available therapies such as combination treatment with rituximab plus standard cytotoxic chemotherapy. The B-cell receptor (BCR) pathway is activated in ABC DLBCL, suggesting that inhibition of this pathway could provide an alternative strategy for treatment. Naquotinib is an irreversible tyrosine kinase inhibitor (TKI) originally designed to target the epidermal growth factor receptor (EGFR). As sequence alignment analysis indicates that irreversible EGFR-TKIs also inhibit Bruton's tyrosine kinase (BTK), here, we characterized the inhibitory effects of naquotinib against BTK in comparison to ibrutinib, acalabrutinib, tirabrutinib and spebrutinib. Naquotinib inhibited BTK kinase activity with similar potency to that for EGFR activating mutations. In vivo, naquotinib induced tumor regression and suppressed tumor recurrence in TMD8 and OCI-Ly10, ABC DLBCL cell line xenograft models, at a lower dose than the clinically relevant dose. Compared to other BTK inhibitors, naquotinib showed faster onset and comparable inhibition of BTK following incubation with cell lines for 3 and 20 h. In addition, naquotinib showed longer continuous inhibition of BTK following removal of the compound, lasting for at least 26 h after removal. Pharmacokinetics studies in the TMD8 xenograft model showed higher concentration and slower elimination of naquotinib in tumors than other BTK inhibitors. These data suggest that naquotinib may have therapeutic potential in ABC DLBCL patients.


Asunto(s)
Linfocitos B/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Piperazinas/uso terapéutico , Piperidinas/uso terapéutico , Pirazinas/uso terapéutico , Pirrolidinas/uso terapéutico , Receptores de Antígenos de Linfocitos B/efectos de los fármacos , Agammaglobulinemia Tirosina Quinasa/genética , Agammaglobulinemia Tirosina Quinasa/metabolismo , Animales , Linfocitos B/inmunología , Linfocitos B/patología , Células Cultivadas , Femenino , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Transgénicos , Piperazinas/farmacocinética , Piperidinas/farmacocinética , Pirazinas/farmacocinética , Pirrolidinas/farmacocinética , Receptores de Antígenos de Linfocitos B/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Bioorg Med Chem ; 17(24): 8161-7, 2009 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-19900813

RESUMEN

A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives were optimized to achieve potent agonistic activity, both in vitro and in vivo, for the arginine vasopressin V(2) receptor, resulting in the eventual discovery of compound 1g. Molecular modeling of compound 1g with V(2) receptor was also examined to evaluate the binding mode of this series of compounds.


Asunto(s)
Acetamidas/farmacología , Arginina Vasopresina/farmacología , Arginina/farmacología , Receptores de Vasopresinas/agonistas , Acetamidas/síntesis química , Animales , Arginina/metabolismo , Arginina Vasopresina/química , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-Actividad
3.
Bioorg Med Chem ; 17(8): 3130-41, 2009 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-19321349

RESUMEN

A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide derivatives was synthesized, and their structure-activity relationships were examined in order to identify potent and selective arginine vasopressin V(2) receptor agonists. Attempts to substitute other chemical groups in place of the 2-pyridilmethyl moiety of 1a led to the discovery that potent V(2) binding affinity could be obtained with a wide range of functional groups. This structural tolerance allowed for the manipulation of other attributes, such as selectivity against V(1a) receptor affinity or avoidance of the undesirable inhibition of cytochrome P450 (CYP), without losing potent affinity for the V(2) receptor. Some representative compounds obtained in this study were also found to decrease urine volume in awake rats.


Asunto(s)
Arginina Vasopresina/metabolismo , Benzamidas/química , Benzamidas/farmacología , Benzazepinas/química , Benzazepinas/farmacología , Receptores de Vasopresinas/agonistas , Animales , Fármacos Antidiuréticos/síntesis química , Fármacos Antidiuréticos/química , Fármacos Antidiuréticos/farmacología , Benzamidas/síntesis química , Benzazepinas/síntesis química , Células CHO , Cricetinae , Cricetulus , Humanos , Estructura Molecular , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores de Vasopresinas/metabolismo , Relación Estructura-Actividad
4.
Mol Cancer Ther ; 18(8): 1366-1373, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31092564

RESUMEN

First- and second-generation EGFR tyrosine kinase inhibitors (TKI) are effective clinical therapies for patients with non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations. However, almost all patients develop resistance to these drugs. The EGFR T790M mutation of EGFR is the most predominant mechanism for resistance. In addition, activation of AXL signaling is one of the suggested alternative bypassing pathways for resistance to EGFR-TKIs. Here, we report that naquotinib, a pyrazine carboxamide-based EGFR-TKI, inhibited EGFR with activating mutations, as well as T790M resistance mutation while sparing wild-type (WT) EGFR. In in vivo murine xenograft models using cell lines and a patient-derived xenograft model, naquotinib induced tumor regression of NSCLC with EGFR-activating mutations with or without T790M resistance mutation, whereas it did not significantly inhibit WT EGFR signaling in skin. Furthermore, naquotinib suppressed tumor recurrence during the treatment period of 90 days. In addition, unlike erlotinib and osimertinib, naquotinib inhibited the phosphorylation of AXL and showed antitumor activity against PC-9 cells overexpressing AXL in vitro and in vivo Our findings suggest that naquotinib has therapeutic potential in patients with NSCLC with EGFR-activating mutations, T790M resistance mutation, and AXL overexpression.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutación , Piperazinas/farmacología , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/genética , Pirazinas/farmacología , Pirrolidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa del Receptor Axl
5.
Bioorg Med Chem ; 16(21): 9524-35, 2008 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-18835174

RESUMEN

The present work describes the discovery of novel series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives as arginine vasopressin (AVP) V(2) receptor agonists. By replacing the amide juncture in YM-35278 with a direct ring connection gave compound 10a, which acts as a V(2) receptor agonist. These studies provided the potent, orally active non-peptidic V(2) receptor agonists 10a and 10j.


Asunto(s)
Arginina Vasopresina/metabolismo , Benzazepinas/síntesis química , Receptores de Vasopresinas/agonistas , Animales , Fármacos Antidiuréticos/síntesis química , Fármacos Antidiuréticos/química , Fármacos Antidiuréticos/farmacología , Benzazepinas/química , Benzazepinas/farmacología , Células CHO , Cricetinae , Cricetulus , Masculino , Estructura Molecular , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores de Vasopresinas/metabolismo , Relación Estructura-Actividad
6.
J Med Chem ; 54(23): 8051-65, 2011 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-21995444

RESUMEN

Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound 1a that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of 1a without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 14i is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.


Asunto(s)
Azepinas/síntesis química , Benzamidas/síntesis química , Inhibidores del Factor Xa , Fibrinolíticos/síntesis química , Administración Oral , Animales , Anticoagulantes/síntesis química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Azepinas/química , Azepinas/farmacología , Benzamidas/química , Benzamidas/farmacología , Disponibilidad Biológica , Dominio Catalítico , Factor Xa/química , Fibrinolíticos/química , Fibrinolíticos/farmacología , Glucurónidos/metabolismo , Humanos , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Ratas , Ratas Endogámicas F344 , Relación Estructura-Actividad
7.
Bioorg Med Chem ; 15(12): 4175-92, 2007 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-17416533

RESUMEN

We describe here our investigation of a new series of orally active fXa inhibitors based on a prodrug strategy. Solid-phase parallel synthesis identified a unique series of fXa inhibitors with a substituted benzenesulfonyl group as a novel S4 binding element. This series resulted in compound 39, which exhibited potent inhibitory activity against fXa (IC50 = 13 nM) and excellent selectivity over thrombin (>7000-fold). The masking of its highly hydrophilic groups led to the creation of related prodrug 28, which demonstrated an anticoagulant effect after oral dosing.


Asunto(s)
Inhibidores del Factor Xa , Profármacos/síntesis química , Profármacos/farmacología , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacología , Animales , Evaluación Preclínica de Medicamentos , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Profármacos/química , Inhibidores de Serina Proteinasa/química , Espectrometría de Masa Bombardeada por Átomos Veloces
8.
Chem Pharm Bull (Tokyo) ; 53(4): 448-50, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15802851

RESUMEN

A practical and cost-effective procedure has been developed for the synthesis of 7-methyl-2-naphthalenecarbonitrile, the precursor of the anticoagulant agents YM-60828 or YM-96765. This new route generates the key intermediate in only two steps from readily available 3-cyanopropionaldehyde dimethyl acetal and m-tolualdehyde, without requiring chromatographic purification. The synthesis involves condensation of the cyano derivative with the aldehyde and subsequent cyclodehydration.


Asunto(s)
Anticoagulantes/síntesis química , Naftalenos/síntesis química , Nitrilos/síntesis química , Benzaldehídos , Cromatografía en Capa Delgada , Compuestos Heterocíclicos/síntesis química , Espectroscopía de Resonancia Magnética , Piperidinas/síntesis química , Espectrofotometría Ultravioleta
9.
Bioorg Med Chem ; 13(4): 1305-23, 2005 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-15670939

RESUMEN

Factor Xa (fXa) is a serine protease that plays a pivotal role in the coagulation cascade. High-throughput screening of the Yamanouchi compound library yielded lead compound 1 with the ability to inhibit fXa at micromolar concentrations. To improve its fXa inhibitory activity and its oral anticoagulant activity, the linker between benzamidine and the central benzene ring was modified and a carboxyl group was introduced at the central benzene ring. The resulting compounds 40b (YM-203552), 41a (YM-202054), and 41c (YM-203558) exhibited potent fXa inhibitory activity and oral anticoagulant activity. In particular, YM-203558 exhibited the most potent oral anticoagulant activity, prolonging PT more than 3-fold at 0.5 and 2.0 h. Additionally, these compounds showed a high degree of selectivity for other serine proteases.


Asunto(s)
Derivados del Benceno/síntesis química , Derivados del Benceno/farmacología , Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacología , Animales , Derivados del Benceno/química , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Modelos Moleculares , Inhibidores de Serina Proteinasa/química , Espectrometría de Masa Bombardeada por Átomos Veloces
10.
Bioorg Med Chem ; 12(9): 2179-91, 2004 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-15080918

RESUMEN

Factor Xa (fXa) is a serine protease involved in the coagulation cascade, which has received great interest as a potential target for the development of new antithrombotic drugs. Herein we report a novel series of fXa inhibitors in which the 1,4-diazepane moiety was designed to interact with the S4 aryl-binding domain of the fXa active site. Compound 13 (YM-96765) showed potent fXa inhibitory activity (IC(50) = 6.8 nM) and effective antithrombotic activity without prolonging bleeding time.


Asunto(s)
Compuestos Aza/química , Inhibidores de Serina Proteinasa/química , Animales , Compuestos Aza/síntesis química , Compuestos Aza/farmacología , Perros , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacología
11.
Bioorg Med Chem ; 10(5): 1509-23, 2002 May.
Artículo en Inglés | MEDLINE | ID: mdl-11886813

RESUMEN

Since Factor Xa (FXa) is well known to play a central role in thrombosis and hemostasis, inhibition of FXa is an attractive target for antithrombotic strategies. As a part of our investigation of a non-peptide, orally available FXa inhibitor, we found that a series of N-[(7-amidino-2-naphthyl)methyl]aniline derivatives possessed potent and selective inhibitory activities. Structure--activity relationship (SAR) of the substituent (R(1)) on the central aniline moiety suggested that increasing lipophilicity caused a detrimental effect on anticoagulant activity (prothrombin time assay) in plasma. Several compounds bearing a hydrophilic substituent in R(1) showed not only potent FXa inhibitory activities but also high anticoagulant activities. The best compound in this series was sulfamoylacetic acid derivative (YM-60828) which was a potent, selective and orally bioavailable FXa inhibitor and was chosen for clinical development.


Asunto(s)
Antitrombina III/farmacología , Inhibidores del Factor Xa , Naftalenos/farmacología , Piperidinas/farmacología , Administración Oral , Animales , Anticoagulantes/administración & dosificación , Anticoagulantes/química , Anticoagulantes/farmacología , Antitrombina III/administración & dosificación , Antitrombina III/química , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Masculino , Ratones , Modelos Moleculares , Naftalenos/administración & dosificación , Naftalenos/química , Piperidinas/administración & dosificación , Piperidinas/química , Tiempo de Protrombina , Relación Estructura-Actividad
12.
Bioorg Med Chem ; 10(8): 2597-610, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12057649

RESUMEN

Factor Xa (FXa) is a serine protease which plays a pivotal role in the coagulation cascade. The inhibition of FXa has received great interest as a potential target for the development of new antithrombotic drug. Herein we describe a series of novel 7-amidino-2-naphthoanilide and 7-amidino-2-naphthalensulfonanilide derivatives which are potent FXa inhibitors. These scaffolds are rigid and are allowed to adopt an L-shape conformation which was estimated as the active conformation based on a docking study of YM-60828 with FXa. Optimization of the side chain at the central aniline nitrogen of 7-amidino-2-naphthoanilide has led to several potent and orally active FXa inhibitors. 5h (YM-169964), the best compound of these series, showed potent FXa inhibitory activity (IC(50)=3.9nM) and effectively prolonged prothrombin time by 9.6-fold ex vivo at an oral dose of 3mg/kg in squirrel monkeys.


Asunto(s)
Anilidas/síntesis química , Anticoagulantes/síntesis química , Inhibidores del Factor Xa , Administración Oral , Anilidas/farmacocinética , Anilidas/farmacología , Animales , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Disponibilidad Biológica , Diseño de Fármacos , Femenino , Masculino , Ratones , Naftalenos/síntesis química , Naftalenos/farmacocinética , Naftalenos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacocinética , Piperidinas/farmacología , Tiempo de Protrombina , Saimiri , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad
13.
Bioorg Med Chem ; 11(3): 367-81, 2003 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-12517432

RESUMEN

Compound YM-60828 was previously characterized in our laboratory as a potent, selective and orally-bioavailable Factor Xa (FXa) inhibitor. The L-shape conformation of this compound in the active site of FXa was recognized as an important factor in displaying its FXa inhibitory activity. This led to the exploration of conformationally restricted cyclic scaffolds bearing a similar active conformation. The current study investigated a novel series of benzothiadiazine-4-one based compounds as FXa inhibitors. Structure-activity relationship (SAR) investigations revealed some potent FXa inhibitors that were selected for further in vitro and ex vivo anticoagulant studies. Among them, compound 6j (YM-169920) was proved to be most effective anticoagulant in this series. The synthesis and SAR in addition to docking studies of this class of inhibitors are described.


Asunto(s)
Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Inhibidores del Factor Xa , Naftalenos/química , Naftalenos/farmacología , Piperidinas/química , Piperidinas/farmacología , Administración Oral , Animales , Anticoagulantes/síntesis química , Anticoagulantes/química , Anticoagulantes/farmacología , Benzotiadiazinas/síntesis química , Disponibilidad Biológica , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Conformación Molecular , Naftalenos/síntesis química , Piperidinas/síntesis química , Tiempo de Protrombina , Saimiri , Relación Estructura-Actividad , Trombina/antagonistas & inhibidores , Inhibidores de Tripsina/síntesis química , Inhibidores de Tripsina/química , Inhibidores de Tripsina/farmacología
14.
Bioorg Med Chem ; 11(7): 1493-502, 2003 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-12628674

RESUMEN

The syntheses and biological evaluation of a series of novel indeno[1,2-d]thiazole derivatives are described. Several groups reported 5-HT(3) receptor agonists which were mainly evaluated for their activities on the von Bezold-Jarisch reflex (B-J reflex). We discovered that tetrahydrothiazolopyridine derivative 1b had a contractile effect on the isolated guinea pig colon with weak B-J reflex. Our efforts to find a new type of 5-HT(3) receptor agonists on the isolated guinea pig colon focused on the synthesis of a fused thiazole derivative 1d modified from 1b and reverse-fused thiazole derivatives (7-10). In this series, 10f (YM-31636) showed high affinity and selectivity for the cloned human 5-HT(3) receptor; furthermore, it showed potent and selective 5-HT(3) receptor agonistic activity. YM-31636 was examined for its effects on defecation in animals, thus evaluating the compound as an agent against constipation.


Asunto(s)
Catárticos/síntesis química , Catárticos/farmacología , Estreñimiento/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Clonación Molecular , Colon/efectos de los fármacos , Defecación/efectos de los fármacos , Hurones , Cobayas , Humanos , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Receptores de Serotonina 5-HT3 , Proteínas Recombinantes/metabolismo , Reflejo/efectos de los fármacos
15.
Bioorg Med Chem ; 12(20): 5415-26, 2004 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-15388168

RESUMEN

Factor Xa (fXa) is a serine protease, which plays a pivotal role in the coagulation cascade. To improve the oral anticoagulant activity of fXa inhibitors containing a 1,4-diazepane moiety as the P4 part, a prodrug strategy was examined. Among the compounds evaluated in this study, amidoxime prodrugs bearing an ester moiety, such as compounds 21 and 30, showed effective oral anticoagulant activity in mice.


Asunto(s)
Amidinas/síntesis química , Amidinas/farmacología , Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Antitrombina III/química , Profármacos/síntesis química , Profármacos/farmacología , Administración Oral , Amidinas/química , Animales , Anticoagulantes/química , Antitrombina III/síntesis química , Antitrombina III/farmacología , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacología , Pruebas de Coagulación Sanguínea , Femenino , Humanos , Ratones , Embarazo
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