RESUMEN
Resistance in Gram-negative bacteria to ß-lactam drugs is mediated primarily by the expression of ß-lactamases, and co-dosing of ß-lactams with a ß-lactamase inhibitor (BLI) is a clinically proven strategy to address resistance. New ß-lactamases that are not impacted by existing BLIs are spreading and creating the need for development of novel broader spectrum BLIs. IID572 is a novel broad spectrum BLI of the diazabicyclooctane (DBO) class that is able to restore the antibacterial activity of piperacillin against piperacillin/tazobactam-resistant clinical isolates. IID572 is differentiated from other DBOs by its broad inhibition of ß-lactamases and the lack of intrinsic antibacterial activity.
Asunto(s)
Compuestos de Azabiciclo/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Inhibidores de beta-Lactamasas/síntesis química , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Farmacorresistencia Microbiana/efectos de los fármacos , Estabilidad de Medicamentos , Bacterias Gramnegativas/enzimología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacologíaRESUMEN
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 synthesis of all four stereoisomers of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid has been developed, thereby significantly shortening the known literature procedures for the syntheses of these unnatural amino acids. With a simple adjustment of the reaction conditions, we were able to obtain either pure cis or trans acid. Optical resolution was accomplished via diastereomeric salt formation or alternatively via chromatography on a chiral stationary phase. Finally, ab initio calculations gave an explanation for the observed cis selectivity in the initial step.
Asunto(s)
Aminoácidos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Ciclohexanos/síntesis química , Aminoácidos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Ciclohexanos/química , Estructura Molecular , Teoría Cuántica , EstereoisomerismoRESUMEN
We have designed and synthesized a novel series of 2,8-diaryl-quinoxalines as Janus kinase 2 inhibitors. Many of the inhibitors show low nanomolar activity against JAK2 and potently suppress proliferation of SET-2 cells in vitro. In addition, compounds from this series have favorable rat pharmacokinetic properties suitable for in vivo efficacy evaluation.
Asunto(s)
Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinoxalinas/química , Quinoxalinas/farmacología , Administración Oral , Animales , Línea Celular , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Quinoxalinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The enantiomers of two different derivatives of tert-leucine were separated by continuous chromatography on chiral stationary phases applying the simulated moving bed technique. About 1 kg of racemic N-carbobenzoxy-tert-leucine was resolved on the cellulose-based phase Chiralcel OD using a mixture of heptane/ethanol and 0.1% of trifluoroacetic acid modifier as the mobile phase, while 520 g of the N-Boc-tert-leucine-benzylester was resolved on the amylose-based phase Chiralpak AD with a mixture of heptane/2-propanol as the mobile phase. In both instances the corresponding enantiomers were obtained in high yield and high optical purity.
