RESUMO
A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c-MYC expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors.
RESUMO
CZ415, a potent ATP-competitive mTOR inhibitor with unprecedented selectivity over any other kinase is described. In addition to a comprehensive characterization of its activities in vitro, in vitro ADME, and in vivo pharmacokinetic data are reported. The suitability of this inhibitor for studying in vivo mTOR biology is demonstrated in a mechanistic mouse model monitoring mTOR proximal downstream phosphorylation signaling. Furthermore, the compound reported here is the first ATP-competitive mTOR inhibitor described to show efficacy in a semitherapeutic collagen induced arthritis (CIA) mouse model.
RESUMO
A series of phenylaminopyrimidines has been identified as inhibitors of Janus kinases (JAKs). Development of this initial series led to the potent JAK2/JAK1 inhibitor CYT387 (N-(cyanomethyl)-4-[2-[[4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]-benzamide). Details of synthesis and SAR studies of these compounds are reported.
Assuntos
Benzamidas/química , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Animais , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Células CACO-2 , Linhagem Celular Tumoral , Simulação por Computador , Humanos , Janus Quinase 2/metabolismo , Masculino , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
[structure: see text] The first asymmetric synthesis of (+)-crocacin D (4) is described. The key steps in the sequence are the stereoselective assembly of the stereotetrad via a substrate-controlled aldol reaction and anti-selective reduction, formation of the (E,E)-diene by a Stille cross-coupling between the stannane 8 and vinyl iodide 9, and the acylation of (Z)-enecarbamate 6 with the acid chloride derived from polyketide fragment 16 which introduced the (Z)-enamide functionality.
