RESUMEN
A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional activities, as well as improved aqueous solubility. Among them, the piperidine 4a showed the best overall profile with favorable PK parameters.
Asunto(s)
Aminas/química , Agonistas del Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Urea/análogos & derivados , Adenosina Difosfato/farmacología , Aminas/síntesis química , Aminas/farmacocinética , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Piperidinas/química , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacocinética , Unión Proteica , Agonistas del Receptor Purinérgico P2Y/síntesis química , Agonistas del Receptor Purinérgico P2Y/farmacocinética , Ratas , Receptores Purinérgicos P2Y1/metabolismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacocinéticaRESUMEN
Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
Asunto(s)
Diseño de Fármacos , Conformación Molecular , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/farmacocinética , Antagonistas del Receptor Purinérgico P2Y/farmacología , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Receptores Purinérgicos P2Y1/metabolismo , Compuestos de Espiro/farmacología , Compuestos de Espiro/farmacocinética , Urea/farmacología , Urea/farmacocinética , Animales , Disponibilidad Biológica , Humanos , Indoles/química , Modelos Moleculares , Compuestos de Fenilurea/química , Compuestos de Fenilurea/metabolismo , Antagonistas del Receptor Purinérgico P2Y/química , Antagonistas del Receptor Purinérgico P2Y/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2Y1/química , Homología de Secuencia de Aminoácido , Compuestos de Espiro/química , Compuestos de Espiro/metabolismo , Urea/química , Urea/metabolismoRESUMEN
Five-membered-ring heterocyclic urea mimics have been found to be potent and selective antagonists of the P2Y1 receptor. SAR of the various heterocyclic replacements is presented, as well as side-chain SAR of the more potent thiadiazole ring system which leads to thiadiazole 4c as a new antiplatelet agent.
Asunto(s)
Antagonistas del Receptor Purinérgico P2Y/química , Antagonistas del Receptor Purinérgico P2Y/farmacología , Receptores Purinérgicos P2Y1/química , Tiadiazoles/química , Tiadiazoles/farmacología , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Humanos , Cinética , Unión Proteica , Relación Estructura-Actividad , Urea/químicaRESUMEN
Diethylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E) and morpholinodifluorosulfinium tetrafluoroborate (XtalFluor-M) are crystalline fluorinating agents that are more easily handled and significantly more stable than Deoxo-Fluor, DAST, and their analogues. These reagents can be prepared in a safer and more cost-efficient manner by avoiding the laborious and hazardous distillation of dialkylaminosulfur trifluorides. Unlike DAST, Deoxo-Fluor, and Fluolead, XtalFluor reagents do not generate highly corrosive free-HF and therefore can be used in standard borosilicate vessels. When used in conjunction with promoters such as Et(3)N.3HF, Et(3)N.2HF, or DBU, XtalFluor reagents effectively convert alcohols to alkyl fluorides and carbonyls to gem-difluorides. These reagents are typically more selective than DAST and Deoxo-Fluor and exhibit superior performance by providing significantly less elimination side products.
Asunto(s)
Boratos/química , Hidrocarburos Fluorados/química , Morfolinas/química , Compuestos de Azufre/química , Temperatura , Boratos/síntesis química , Halogenación , Hidrocarburos Fluorados/síntesis química , Estructura Molecular , Morfolinas/síntesis química , Sales (Química)/síntesis química , Sales (Química)/química , Estereoisomerismo , Compuestos de Azufre/síntesis químicaRESUMEN
Aminodifluorosulfinium tetrafluoroborate salts were found to act as efficient deoxofluorinating reagents when promoted by an exogenous fluoride source and, in most cases, exhibited greater selectivity by providing less elimination byproduct as compared to DAST and Deoxo-Fluor. Aminodifluorosulfinium tetrafluoroborates are easy handled crystalline salts that show enhanced thermal stability over dialkylaminosulfur trifluorides, are storage-stable, and unlike DAST and Deoxo-Fluor do not react violently with water.
Asunto(s)
Boratos/química , Hidrocarburos Fluorados/síntesis química , Ácidos Sulfínicos/química , Catálisis , Técnicas Químicas Combinatorias , Hidrocarburos Fluorados/química , Indicadores y Reactivos , Estructura Molecular , Sales (Química) , Agua/químicaRESUMEN
We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Diseño de Fármacos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirroles/farmacología , Triazinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/síntesis química , Animales , Línea Celular , Inhibidores del Citocromo P-450 CYP3A , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Pirroles/síntesis química , Relación Estructura-Actividad , Triazinas/síntesis química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Replacement of the morpholinyl moiety in (S,E)-N-[1-(3-morpholinophenyl)ethyl]-3-phenylacrylamide (1) with heteroaryl groups led to the identification of (S,E)-N-1-[3-(6-fluoropyridin-3-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (5) as a potent KCNQ2 potassium channel opener. Among this series of heteroaryl substituted acrylamides, (S,E)-N-1-[3-(1H-pyrazol-1-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (9) exhibits balanced potency and efficacy. The syntheses and the KCNQ2 opener activity of this series of acrylamides are described.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/metabolismo , Acrilamidas/síntesis química , Acrilamidas/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Canal de Potasio KCNQ2 , Estructura MolecularRESUMEN
A new class of acrylamides was synthesized, and the effects of these analogues on outward potassium current were evaluated by using two electrode voltage clamp recordings from Xenopus laevis oocytes expressing cloned mKCNQ2 channels. SAR studies indicated that the pharmacophore of the acrylamide series includes the (S) absolute configuration at the (1-phenyl)ethyl moiety and the alpha,beta-unsaturated acrylamide functionality with a free NH. This study identified (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide ((S)-1) and (S)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-fluoro-phenyl)-acrylamide ((S)-2) as KCNQ2 openers for further electrophysiological evaluations. These two acrylamides demonstrated significant activity in the cortical spreading depression model of migraine as we reported previously.
Asunto(s)
Acrilamidas/síntesis química , Cinamatos/síntesis química , Morfolinas/síntesis química , Canales de Potasio/efectos de los fármacos , Acrilamidas/química , Acrilamidas/farmacología , Animales , Cinamatos/química , Cinamatos/farmacología , Depresión de Propagación Cortical/efectos de los fármacos , Humanos , Canal de Potasio KCNQ2 , Ratones , Morfolinas/química , Morfolinas/farmacología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Canales de Potasio/fisiología , Canales de Potasio con Entrada de Voltaje , Estereoisomerismo , Relación Estructura-Actividad , Xenopus laevisRESUMEN
An asymmetric total synthesis of (+)-chatancin was achieved via a transannular Diels-Alder (TADA) reaction of an in situ generated macrocyclic pyranophane pseudobase. The presented route constitutes the second of two proposed biosynthetic pathways that involves a TADA reaction. It links this diterpene biogenetically to the cembranoids. A set of TADA selection rules that rationalize the formation of (+)-chatancin from a dynamic equilibrium of four 2-hydroxy-2H-pyrane bicycles and their 16 potential TADA transition states are also outlined. Beyond the TADA reaction, highlights of the synthetic work include the assembly of a chiral acyclic macrocyclization substrate from (S)-citronellol and an efficient macrocyclization via a beta-ketosulfoxyde/enone Michael addition.
Asunto(s)
Diterpenos/síntesis química , Piranos/química , Biomimética/métodos , Ciclización , Diterpenos/química , Furanos/química , EstereoisomerismoRESUMEN
Two routes describing the preparation of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (4a) from 1H-pyrrolo[2,3-b]pyridine N-oxide (1) are presented. Regioselective fluorination was achieved using either the Balz-Schiemann reaction or lithium-halogen exchange. [reaction: see text]
RESUMEN
(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide (2) was synthesized as an orally bioavailable KCNQ2 potassium channel opener. In a rat model of migraine, 2 demonstrated significant oral activity in reducing the total number of cortical spreading depressions induced by potassium chloride.