RESUMEN
Potent and selective thrombin inhibitors have been prepared with a piperazinedione template and L-amino acids. Likewise, incorporation of D-amino acids led to potent inhibitors with a novel mode of binding. Herein, the structure activity relationships and structural aspects of these compounds will be described.
Asunto(s)
Antitrombinas/síntesis química , Diseño de Fármacos , Piperazinas/síntesis química , Antitrombinas/química , Antitrombinas/farmacología , Cristalografía por Rayos X , Estructura Molecular , Piperazinas/química , Piperazinas/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors are described. We have explored the SAR around the P1' site. Modification of the P1' site has been found to affect potency and selectivity.
Asunto(s)
Lactamas/farmacología , Trombina/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Compuestos Heterocíclicos/química , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Modelos Moleculares , Ratas , Trombosis/tratamiento farmacológicoRESUMEN
The development of benzothiazine-1,1-dioxide derivatives as a new structural class of potent endothelin receptor antagonists is described. Structure-activity relationships (SAR) revealed that PD164800 (1) is a potent antagonist of the ETA receptor subtype.
Asunto(s)
Dioxoles/síntesis química , Antagonistas de los Receptores de Endotelina , Tiazinas/síntesis química , Animales , Células CHO , Cricetinae , Dioxoles/química , Dioxoles/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-Actividad , Tiazinas/química , Tiazinas/farmacologíaRESUMEN
Peptidomimetic inhibitors of general structure 1 have been prepared. Optimization of the binding affinities of these compounds through variation of the P3 hydrophobic residue is described. Selected substituted bicylic lactams displayed interesting pharmacological profiles both in vitro and in vivo.
Asunto(s)
Fibrinolíticos/síntesis química , Lactamas/síntesis química , Inhibidores de Serina Proteinasa/síntesis química , Trombina/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Fibrinolíticos/farmacología , Lactamas/farmacología , Ratas , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.
Asunto(s)
Fibrinolíticos/síntesis química , Lactamas/síntesis química , Inhibidores de Serina Proteinasa/síntesis química , Trombina/antagonistas & inhibidores , Animales , Fibrinolíticos/farmacología , Lactamas/farmacología , Ratas , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
The design of potent and selective non-peptide antagonists of endothelin-1 (ET-1) and its related isopeptides are important tools defining the role of ET in human diseases. In this report we will describe the detailed structure-activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ETA selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET(A) selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ETA selective antagonist PD156707, IC50's = 0.3 (ET(A)) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ETA receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ETA mediated) with a pA2 = 7.6. PD156707 also displayed in vivo functional activity inhibiting the hemodynamic responses due to exogenous administration of ET-1 in rats in a dose dependent fashion. Evidence for the pH dependence of the open and closed tautomerization forms of PD156707 was demonstrated by an NMR study. X-ray crystallographic analysis of the closed butenolide form of PD156707 shows the benzylic group located on the same side of the butenolide ring as the gamma-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmacokinetic parameters for PD156707 in dogs are also presented.
Asunto(s)
Dioxoles/farmacología , Endotelina-1/antagonistas & inhibidores , Administración Oral , Animales , Área Bajo la Curva , Dioxoles/química , Dioxoles/farmacocinética , Perros , Humanos , Espectroscopía de Resonancia Magnética , Conejos , Ratas , Relación Estructura-ActividadAsunto(s)
Dioxoles/farmacología , Antagonistas de los Receptores de Endotelina , Administración Oral , Animales , Clonación Molecular , Dioxoles/administración & dosificación , Dioxoles/farmacocinética , Humanos , Masculino , Péptidos/farmacología , Conejos , Ratas , Ratas Wistar , Receptor de Endotelina A , Receptores de Endotelina/genética , Relación Estructura-ActividadRESUMEN
The development of nonpeptide, low molecular weight antagonists with high potency, oral activity, and selectivity is an important objective to adequately define the potential role of endothelin (ET) and its isopeptides in human diseases. This report describes the structure-activity relationships, ETA/ETB selectivity, and pharmacokinetics of the PD 155080 and PD 156707 series of orally active nonpeptide ET receptor-selective antagonists. Modification of the substituents around the butenolide ring has led to compounds with differing selectivity for human ETA and ETB receptors. Thus, compounds with increased lipophilicity at R2 show increased ETB affinity and a more balanced ETA/ETB profile. For example, the 4-O-n-pentyl analogue of PD 156707 is a potent competitive inhibitor of [125I]ET-1 and [125I]ET-3 binding to human cloned ETA and ETB receptors, with IC50s of 0.8 nM and 44 nM, respectively. Pharmacokinetic properties can also be significantly influenced by structural modifications at the R2 group. The pharmacokinetics of PD 155719, PD 155080, and PD 156707 were compared in male Wistar rats after a 15 mg/kg intravenous or oral gavage dose (three animals per dose). Plasma concentrations were determined by a specific HPLC assay. Oral bioavailability ranged from less than 5% for PD 155719 to 41% for PD 156707 and 87% for PD 155080.