RESUMO
Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2.
Assuntos
Descoberta de Drogas , Imidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Pirimidinas/farmacologia , Quinase 1 do Ponto de Checagem , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pirazinas/síntese química , Pirazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
Drug design efforts in the emerging 2-aminothiazole-4-carboxamide class of CHK1 inhibitors have uncovered specific combinations of key substructures within the molecule; resulting in significant improvements in cell-based activity while retaining a greater than one hundred-fold selectivity against CDK2. The X-ray crystal structure of a complex between compound 39 and the CHK1 protein detailing a 'U-shaped' topology and key interactions with the protein surface at the ATP site is also reported.
Assuntos
Amidas/química , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Tiazóis/química , Amidas/síntese química , Amidas/metabolismo , Sítios de Ligação , Quinase 1 do Ponto de Checagem , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
Antibiotic resistant hospital acquired infections are on the rise, creating an urgent need for novel bactericidal drugs. Enzymes involved in lipopolysaccharide (LPS) biosynthesis are attractive antibacterial targets since LPS is the major structural component of the outer membrane of Gram-negative bacteria. Lipid A is an essential hydrophobic anchor of LPS and the first committed step in lipid A biosynthesis is catalyzed by a unique zinc dependent metalloamidase, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). LpxC is an attractive Gram-negative only target that has been chemically validated by potent bactericidal hydroxamate inhibitors that work by coordination of the enzyme's catalytic zinc ion. An exploratory chemistry effort focused on expanding the SAR around hydroxamic acid zinc-binding 'warheads' lead to the identification of novel compounds with enzyme potency and antibacterial activity similar to CHIR-090.
Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/síntese química , Bactérias Gram-Negativas/efeitos dos fármacos , Amidoidrolases/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Benzodiazepinonas/química , Sítios de Ligação , Catálise , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Ácidos Hidroxâmicos/química , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Zinco/químicaRESUMO
Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.