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
Based on the lead compound BX-517, a series of C-4' substituted indolinones have been synthesized and evaluated for PDK1 inhibition. Modification at C-4' of the pyrrole afforded potent compounds (7b and 7d) with improved solubility and ADME properties. In this letter, we describe the synthesis, selectivity profile, and pharmacokinetic data of selected compounds.
Asunto(s)
Indoles/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Urea/análogos & derivados , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Línea Celular Tumoral , Humanos , Indoles/farmacología , Inhibidores de Proteínas Quinasas/química , Urea/química , Urea/farmacologíaRESUMEN
A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.
Asunto(s)
Amidas/farmacología , Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/farmacología , Tiofenos/química , Amidas/química , Animales , Cristalografía por Rayos X , Perros , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Modelos Moleculares , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-ActividadRESUMEN
A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined.
