RESUMO
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.
Assuntos
Compostos Azabicíclicos/síntese química , Bactérias Gram-Negativas/efeitos dos fármacos , Inibidores de beta-Lactamases/síntese química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Estabilidade de Medicamentos , Bactérias Gram-Negativas/enzimologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologiaRESUMO
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.
Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Imidazóis/farmacologia , Rim/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirrolidinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Sistema Cardiovascular/metabolismo , Humanos , Imidazóis/química , Rim/metabolismo , Testes de Função Renal , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pirrolidinas/química , Ratos , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas/químicaRESUMO
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.
Assuntos
Aminoácidos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Cicloexanos/síntese química , Aminoácidos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Cicloexanos/química , Estrutura Molecular , Teoria Quântica , EstereoisomerismoRESUMO
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.
Assuntos
Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Administração Oral , Animais , Linhagem Celular , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacocinética , Quinoxalinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
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.
