RESUMEN
The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Imidazoles/farmacología , Riñón/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirrolidinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Sistema Cardiovascular/metabolismo , Humanos , Imidazoles/química , Riñón/metabolismo , Pruebas de Función Renal , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Pirrolidinas/química , Ratas , Ratas Sprague-Dawley , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
A series of glycoconjugates with defined connectivity were synthesized to investigate the impact of coupling Salmonella typhimurium O-antigen to different amino acids of CRM197 protein carrier. In particular, two novel methods for site-selective glycan conjugation were developed to obtain conjugates with single attachment site on the protein, based on chemical modification of a disulfide bond and pH-controlled transglutaminase-catalyzed modification of lysine, respectively. Importantly, conjugation at the C186-201 bond resulted in significantly higher anti O-antigen bactericidal antibody titers than coupling to K37/39, and in comparable titers to conjugates bearing a larger number of saccharides. This study demonstrates that the conjugation site plays a role in determining the immunogenicity in mice and one single attachment point may be sufficient to induce high levels of bactericidal antibodies.
Asunto(s)
Glicoconjugados/química , Glicoconjugados/inmunología , Antígenos O/química , Antígenos O/inmunología , Vacunas contra la Salmonella/química , Vacunas contra la Salmonella/inmunología , Salmonella typhimurium/inmunología , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Conformación Molecular , Salmonella typhimurium/químicaRESUMEN
Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hipertrigliceridemia/sangre , Piperidinas/farmacología , Anciano , Animales , Embrión de Pollo , Humanos , Masculino , Mesocricetus , Piperidinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compound reduced blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats (SHR), confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.
Asunto(s)
Antihipertensivos/farmacología , Hipertensión/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Tiazoles/farmacología , Regulación Alostérica , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacocinética , Células HEK293 , Humanos , Masculino , Ratones Transgénicos , Antígenos de Histocompatibilidad Menor , Simulación del Acoplamiento Molecular , Piperazinas/síntesis química , Piperazinas/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinética , Proteína Quinasa Deficiente en Lisina WNK 1RESUMEN
The stereoselective and chiral synthesis of the Amaryllidaceae alkaloid, (+)-vittatine 1, is described; the quaternary carbon in 1 was generated by Claisen rearrangement of a cyclohexenol derived from D-glucose by way of a Ferrier's carbocyclisation reaction and a hexahydroindole skeleton was effectively constructed by intramolecular aminomercuration-demercuration, followed by Chugaev reaction.
Asunto(s)
Alcaloides/química , Alcaloides/síntesis química , Carbohidratos/química , Fenantridinas/química , Fenantridinas/síntesis química , Ciclización , Estructura Molecular , EstereoisomerismoRESUMEN
A cationic palladium(II)/(S)-xyl-Segphos complex catalyzes enantioselective cycloisomerizations of N-alkenyl arylethynylamides leading to axially chiral 4-aryl-2-pyridones in high yields with high ee values. The present catalysis represents the first enantioselective construction of axial chirality by the transition-metal-catalyzed cycloisomerization.
Asunto(s)
Alquenos/química , Alquinos/química , Paladio/química , Piridonas/síntesis química , Catálisis , Técnicas Químicas Combinatorias , Ciclización , Estructura Molecular , Piridonas/química , EstereoisomerismoRESUMEN
A new method for the convergent and rapid assembly of substituted 2-pyridones was developed through the formation of N-alkenyl alkynylamides (amide-linked 1,5-enynes) by N-acylation of imines with alkynoyl chlorides and the subsequent cationic Au(I)/PPh 3-catalyzed cycloisomerization.