RESUMEN
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
Asunto(s)
Amidas/síntesis química , Aminopiridinas/síntesis química , Anticoagulantes/síntesis química , Inhibidores del Factor Xa , Tiofenos/síntesis química , ortoaminobenzoatos/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Animales , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Cristalografía por Rayos X , Perros , Humanos , Técnicas In Vitro , Masculino , Modelos Moleculares , Tiempo de Protrombina , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacología , Trombosis de la Vena/tratamiento farmacológico , ortoaminobenzoatos/farmacocinética , ortoaminobenzoatos/farmacologíaRESUMEN
High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.
Asunto(s)
Fármacos Anti-VIH/química , Antiinflamatorios no Esteroideos/química , Antagonistas de los Receptores CCR5 , Mitoguazona/análogos & derivados , Fármacos Anti-VIH/síntesis química , Antiinflamatorios no Esteroideos/síntesis química , Células Cultivadas , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.
Asunto(s)
Indoles/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Diseño de Fármacos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis químicaRESUMEN
Reductive amination followed by acylation of polymer-linked formyl aryl amidines generate combinatorial libraries of aryl amidines 8-13. Potent small molecule naphthylamidine inhibitors 12 (Ki<100 nM) of FVIIa/TF have been discovered and their activity against other serine proteases in the coagulation cascade is reported.
Asunto(s)
Amidinas/síntesis química , Factor VIIa/antagonistas & inhibidores , Tromboplastina/antagonistas & inhibidores , Amidinas/química , Amidinas/farmacología , Sitios de Unión , Humanos , Cinética , Modelos Moleculares , Conformación Molecular , Naftoles/síntesis química , Naftoles/química , Naftoles/farmacología , Relación Estructura-ActividadRESUMEN
The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors through interactions with the S1'/S2' pocket.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Factor VIIa/química , Fibrinolíticos/síntesis química , Piridinas/síntesis química , Tromboplastina/química , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Factor VIIa/antagonistas & inhibidores , Inhibidores del Factor Xa , Fibrinolíticos/química , Fibrinolíticos/farmacología , Humanos , Concentración 50 Inhibidora , Unión Proteica , Tiempo de Protrombina , Piridinas/química , Relación Estructura-Actividad , Tromboplastina/antagonistas & inhibidoresRESUMEN
Compound 2 was identified by high throughput screening as a novel PAI-1 inhibitor. Systematic optimization of the A, B, and C segments of 2 resulted in the identification of a more potent compound 39 with good oral bioavailability. The synthesis and SAR data are presented in this report.
Asunto(s)
Piperazinas/síntesis química , Piperazinas/farmacología , Inhibidor 1 de Activador Plasminogénico/química , Animales , Pruebas de Coagulación Sanguínea , Evaluación Preclínica de Medicamentos , Fibrinólisis/efectos de los fármacos , Estructura Molecular , Inhibidor 1 de Activador Plasminogénico/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A novel potent and selective aminophenol scaffold for fXa inhibitors was developed from a previously reported benzimidazole-based naphthylamidine template. The aminophenol template is more synthetically accessible than the benzimidazole template, which simplified the introduction of carboxylic acid groups. Substitution of a propenyl-para-hydroxy-benzamidine group on the aminophenol template produced selective, sub-nanomolar fXa inhibitors. The potency of the inhibitors is partially explained with the aid of a trypsin complex crystal structure.
Asunto(s)
Aminofenoles/química , Aminofenoles/síntesis química , Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/síntesis química , Difracción de Rayos XRESUMEN
Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.