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1.
Bioorg Med Chem ; 21(18): 5907-22, 2013 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-23886807

RESUMEN

We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P1', P2' and P3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys.


Asunto(s)
Amidas/química , Piperazinas/síntesis química , Piperidinas/química , Piperidinas/síntesis química , Inhibidores de Proteasas/síntesis química , Renina/antagonistas & inhibidores , Administración Oral , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Furosemida/farmacología , Semivida , Hipertensión/tratamiento farmacológico , Macaca fascicularis , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , Ratas , Ratas Transgénicas , Renina/metabolismo , Relación Estructura-Actividad
2.
Bioorg Med Chem ; 21(11): 3175-96, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23598247

RESUMEN

With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.


Asunto(s)
Antihipertensivos/síntesis química , Arritmias Cardíacas/prevención & control , Corazón/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Piperazinas/síntesis química , Inhibidores de Proteasas/síntesis química , Renina/antagonistas & inhibidores , Administración Oral , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Presión Arterial/efectos de los fármacos , Femenino , Corazón/fisiopatología , Humanos , Hipertensión/enzimología , Hipertensión/fisiopatología , Macaca fascicularis , Masculino , Técnicas de Cultivo de Órganos , Piperazinas/farmacocinética , Piperazinas/farmacología , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Conejos , Ratas , Renina/química , Renina/metabolismo , Relación Estructura-Actividad
4.
Bioorg Med Chem Lett ; 21(24): 7337-43, 2011 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-22044620

RESUMEN

We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administration test. In vitro and oral activities were improved by optimization of S1 and S4 ligands. Incorporating the interaction with S1-ß pocket enhanced in vitro factor Xa inhibitory activity to less than 1 nM. Many zwitter ionic compounds showed long duration of action and potent inhibitory activity and high AUC values in oral administration tests to monkeys.


Asunto(s)
Anticoagulantes/química , Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/química , Administración Oral , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/farmacocinética , Animales , Anticoagulantes/síntesis química , Anticoagulantes/farmacocinética , Sitios de Unión , Simulación por Computador , Factor Xa/metabolismo , Haplorrinos , Iones/química , Estructura Terciaria de Proteína , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 21(7): 2133-40, 2011 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-21345673

RESUMEN

We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30 h which showed both good in vitro activity (fXa IC(50) = 2.2 nM, PTCT2 = 3.9 µM) and in vivo antithrombotic efficacy.


Asunto(s)
Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Modelos Moleculares , Inhibidores de Serina Proteinasa/síntesis química , Relación Estructura-Actividad
6.
Bioorg Med Chem ; 19(5): 1623-42, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21316975

RESUMEN

We have been researching orally active factor Xa inhibitor for a long time. We explored the new diamine linker using effective ligands to obtain a new attractive original scaffold 2-aminomethylphenylamine derivative. Compound 1D showed very strong in vitro and in vivo factor Xa inhibitory activity, as well as favorable PK profiles in po administration to monkeys.


Asunto(s)
Compuestos de Anilina/química , Compuestos de Anilina/síntesis química , Inhibidores de Factor de Coagulación Sanguínea/síntesis química , Inhibidores del Factor Xa , Animales , Inhibidores de Factor de Coagulación Sanguínea/química , Cristalografía por Rayos X , Haplorrinos , Humanos , Concentración 50 Inhibidora , Ligandos , Estructura Molecular , Ratas
7.
Bioorg Med Chem ; 17(24): 8221-33, 2009 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-19900814

RESUMEN

A series of cis-1,2-diaminocyclohexane derivatives possessing a 6-6 fused ring for the S1 moiety were synthesized as novel factor Xa (fXa) inhibitors. The synthesis, structure-activity relationship (SAR), and physicochemical properties are reported herein, together with the discovery of compound 45c, which has potent anti-fXa activity, good physicochemical properties and pharmacokinetic (PK) profiles, including a reduced negative food effect.


Asunto(s)
Anticoagulantes/química , Ciclohexilaminas/química , Diseño de Fármacos , Anticoagulantes/farmacología , Antitrombina III/uso terapéutico , Sitios de Unión , Ciclohexilaminas/farmacología , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad
8.
Bioorg Med Chem ; 17(24): 8206-20, 2009 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-19884015

RESUMEN

A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.


Asunto(s)
Anticoagulantes/uso terapéutico , Antitrombina III/uso terapéutico , Ciclohexilaminas/uso terapéutico , Diseño de Fármacos , Administración Oral , Sitios de Unión , Unión Competitiva , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Absorción Intestinal/efectos de los fármacos , Cinética , Estructura Molecular , Glicoproteínas de Membrana Plaquetaria , Conformación Proteica , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 18(2): 782-7, 2008 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-18039572

RESUMEN

Previously, we identified cyclohexane diamine derivative 1 as orally bioavailable factor Xa inhibitor. We have investigated two racemic cis-piperidine diamine derivatives 2 and 3 based on 1. Compounds 2a-e showed higher fXa inhibitory activity, anticoagulant activity, and aqueous solubility than 3a-e having same substituent. Compounds 2a, 2c, 2e, and 2g-m having sp2 nitrogen, especially amide and urea derivatives, showed potent anticoagulant activity. Compounds 2h and 2k showed high oral activities in rats.


Asunto(s)
Inhibidores del Factor Xa , Piperidinas/química , Piperidinas/farmacología , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Administración Oral , Animales , Área Bajo la Curva , Diaminas/química , Diseño de Fármacos , Haplorrinos , Humanos , Microsomas Hepáticos/metabolismo , Piperidinas/administración & dosificación , Piperidinas/síntesis química , Ratas , Inhibidores de Serina Proteinasa/administración & dosificación , Inhibidores de Serina Proteinasa/síntesis química
10.
Bioorg Med Chem ; 14(5): 1309-30, 2006 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-16263291

RESUMEN

Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.


Asunto(s)
Anticoagulantes/farmacología , Antitrombina III , Coagulación Sanguínea/efectos de los fármacos , Péptidos/química , Inhibidores de Serina Proteinasa/farmacología , Administración Oral , Animales , Anticoagulantes/síntesis química , Antitrombina III/síntesis química , Antitrombina III/metabolismo , Antitrombina III/farmacología , Sitios de Unión , Pruebas de Coagulación Sanguínea , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Ligandos , Microsomas Hepáticos/metabolismo , Péptidos/metabolismo , Ratas , Relación Estructura-Actividad
11.
Bioorg Med Chem ; 13(12): 3927-54, 2005 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-15911309

RESUMEN

Compound 7 was identified as the active metabolite of 6 by HPLC and mass spectral analysis. Modification of lead compound 7 by transformation of its N-oxide 6-6 biaryl ring system and fused aromatics produced a series of non-basic fXa inhibitors with excellent potency in anti-fXa and anticoagulant assays. The optimized compounds 73b and 75b showed sub to one digit micromolar anticoagulant activity (PTCT2). Particularly, anti-fXa activity was detected in plasma of rats orally administered with 1mg/kg of compound 75b.


Asunto(s)
Anticoagulantes/síntesis química , Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacocinética , Administración Oral , Animales , Anticoagulantes/farmacología , Sitios de Unión , Coagulación Sanguínea/efectos de los fármacos , Pruebas de Coagulación Sanguínea , Diseño de Fármacos , Humanos , Absorción Intestinal , Ratas , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad
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