RESUMO
The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.
Assuntos
Desenho de Fármacos , Isoquinolinas/química , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Sítios de Ligação , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Simulação de Dinâmica Molecular , Proteínas Nucleares/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismoRESUMO
A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC50 of 25 nM in the replicon cell-based assay.
Assuntos
Antivirais/síntese química , Ácidos Borônicos/síntese química , Proteínas de Transporte/antagonistas & inibidores , Hepacivirus/efeitos dos fármacos , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
The synthesis and biochemical evaluation of novel cyanothiazolidine inhibitors of dipeptidyl peptidase 4 (DPP4) is described. Their main structural feature is a constrained bicyclic core that prevents the intramolecular formation of inactive cyclic species. The inhibitors show good to moderate biochemical potency against DPP4 and display distinct selectivity profiles towards DPP7, DPP8 and DPP9 depending on their substitution.
Assuntos
Compostos Azabicíclicos/síntese química , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores Enzimáticos/síntese química , Nitrilas/síntese química , Tiazolidinas/síntese química , Compostos Azabicíclicos/farmacologia , Catálise , Diabetes Mellitus/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Nitrilas/farmacologia , Estrutura Terciária de Proteína , Pirrolidinas/química , Relação Estrutura-Atividade , Tiazóis/química , Tiazolidinas/farmacologia , Fatores de TempoRESUMO
The synthesis and biochemical characterization of AX4697, a fluorescent, bisindolylmaleimide-derived probe for PKCalpha and beta, is described. AX4697 was able to quantify changes in PKC expression in drug-treated Jurkat cells and was shown to covalently label PKCalpha on C619, a residue that sits just outside the active site.
Assuntos
Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Indóis/síntese química , Indóis/farmacologia , Maleimidas/síntese química , Maleimidas/farmacologia , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C/metabolismo , Domínio Catalítico , Desenho de Fármacos , Corantes Fluorescentes/química , Humanos , Indóis/química , Células Jurkat , Maleimidas/química , Estrutura Molecular , Proteína Quinase C beta , Relação Estrutura-AtividadeRESUMO
The intramolecular attack of a hydroxy group on an exo-biscobalthexacarbonyl propargylic cation provides cyclic ethers with six- to nine-membered rings. The scope and limitations of the methodology are described. The reaction is stereoselective when additional stereocenters are present, providing iterative methodology to access ladder-like cyclic ethers.
RESUMO
The development of syntheses providing enantiomerically pure alpha-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized alpha-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected alpha-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized alpha-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values of > or = 99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operationally simple reaction conditions. The keto-functionality present in the products provides a particularly attractive site for versatile modifications. This study compliments and extends our bioorganic approach to asymmetric synthesis to a versatile synthon class. Given that we have shown that a variety of optically active amino acids can be synthesized with proline catalysis, where an L-amino acid begets other L-amino acids, our results may stimulate thoughts concerning prebiotic syntheses of optically active amino acids based on this route.