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-ActividadRESUMEN
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-ActividadRESUMEN
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 , RatasRESUMEN
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-ActividadRESUMEN
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-ActividadRESUMEN
In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity.
Asunto(s)
Anticoagulantes/química , Anticoagulantes/farmacología , Inhibidores del Factor Xa , Indoles/farmacología , Propionatos/farmacología , Tiazoles/farmacología , Administración Oral , Animales , Anticoagulantes/síntesis química , Disponibilidad Biológica , Cristalografía por Rayos X , Factor Xa/metabolismo , Haplorrinos , Humanos , Indoles/química , Indoles/farmacocinética , Naftalenos/síntesis química , Naftalenos/química , Naftalenos/farmacología , Propionatos/síntesis química , Propionatos/química , Propionatos/farmacocinética , Unión Proteica , Tiazoles/química , Tiazoles/farmacocinéticaRESUMEN
There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.
Asunto(s)
Benzotiazoles/síntesis química , Ácidos Carboxílicos/farmacología , Ciclohexilaminas/síntesis química , Inhibidores del Factor Xa , Animales , Anticoagulantes/farmacología , Antitrombina III/química , Antitrombina III/farmacología , Benzotiazoles/farmacología , Coagulación Sanguínea/efectos de los fármacos , Ácidos Carboxílicos/química , Química Farmacéutica/métodos , Ciclohexanos/química , Ciclohexilaminas/farmacología , Diseño de Fármacos , Factor Xa/química , Concentración 50 Inhibidora , Modelos Químicos , Inhibidores de Serina Proteinasa/síntesis química , Estereoisomerismo , Factores de TiempoRESUMEN
This paper describes the synthesis of orally available potent fXa inhibitors 2 and 3 by modification of the piperazine part of lead compound 1. Carbonyl derivative 3 showed potent fXa activity but not sulfonyl derivative 2. Among the compounds synthesized, cyclohexane derivatives 3g and 3h and cycloheptane derivative 3j had potent anticoagulant activity as well as anti-fXa activity. Synthetic study of the optical isomers of 3g demonstrated that (-)-3g had more potent activity.