RESUMO
A vinyl azide cyclization method was used to synthesize three different carbocyclic[g]indole scaffolds as inhibitors of human nonpancreatic secretory phospholipase A2. Each scaffold demonstrated potent enzyme activity in a chromogenic assay system, with select examples also demonstrating potent activity in a secondary DOC/PC assay. Compound 11, representative of the cyclopent[g]indole series, gave an IC50 of 10 nM for the inhibition of hnps-PLA2 in the chromogenic assay.
Assuntos
Acetatos/síntese química , Ciclopentanos/síntese química , Indóis/síntese química , Fosfolipases A/antagonistas & inibidores , Acetatos/química , Ciclopentanos/química , Humanos , Indóis/química , Fosfolipases A/química , Fosfolipases A2 , Relação Estrutura-AtividadeRESUMO
2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) potentiators are ligands that act as positive allosteric modulators at the AMPA receptors. We recently disclosed a novel series of 2-arylpropylsulfonamides that were potent potentiators of responses mediated through AMPA receptors. To further define the structural requirements for activity in this series, new ring-constrained analogues were prepared and a new stereocenter was introduced. The potentiating activity was highly dependent on the stereochemistry at the 2-position of the disubstituted cyclopentane and was independent of the relative stereochemistry at the 1-position. Compound (R,R)-10 represents a potent, novel potentiator of iGluR4 flip receptors (EC(50) = 22.6 nM).
Assuntos
Ciclopentanos/síntese química , Fármacos Atuantes sobre Aminoácidos Excitatórios/síntese química , Receptores de AMPA/efeitos dos fármacos , Sulfonamidas/síntese química , Linhagem Celular , Ciclopentanos/química , Ciclopentanos/farmacologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/química , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/farmacologia , Humanos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.
Assuntos
Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Células 3T3 , Trifosfato de Adenosina/metabolismo , Animais , Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Inibidores Enzimáticos/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Vison , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Modelos Moleculares , Proteínas Serina-Treonina Quinases/química , Estrutura Terciária de Proteína , Pirazóis/química , Pirazóis/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/química , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Spodoptera , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TbetaR-I receptor kinase domain.