RESUMO
The IC50 of a beta-secretase (BACE-1) lead compound was improved â¼200-fold from 11 µM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Hidantoínas/química , Hidantoínas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Hidantoínas/síntese química , Metilação , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
This communication reports a new synthetic route of pyridopyrimidines to facilitate their structural optimization in a library fashion and describes the development of pyridopyrimidines that have excellent enzymatic and cell potency against Akt1 and Akt2. This series also shows a high level of selectivity over other closely related kinases and significantly improved caspase-3 activity with the more optimized compounds.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Relação Estrutura-Atividade , Ligante Indutor de Apoptose Relacionado a TNF/farmacologiaRESUMO
The kinesin spindle protein (KSP, also known as Eg5) is essential for the proper separation of spindle poles during mitosis, and inhibition results in mitotic arrest and the formation of characteristic monoaster spindles. Several distinct classes of KSP inhibitors have been described previously in the public and patent literature. However, most appear to share a common induced-fit allosteric binding site, suggesting a common mechanism of inhibition. In a high-throughput screen for inhibitors of KSP, a novel class of thiazole-containing inhibitors was identified. Unlike the previously described allosteric KSP inhibitors, the thiazoles described here show ATP competitive kinetic behavior, consistent with binding within the nucleotide binding pocket. Although they bind to a pocket that is highly conserved across kinesins, these molecules exhibit significant selectivity for KSP over other kinesins and other ATP-utilizing enzymes. Several of these compounds are active in cells and produce a phenotype similar to that observed with previously published allosteric inhibitors of KSP.
Assuntos
Trifosfato de Adenosina/metabolismo , Bioquímica/métodos , Cinesinas/antagonistas & inibidores , Cinesinas/química , Mitose , Trifosfato de Adenosina/química , Sítio Alostérico , Ligação Competitiva , Desenho de Fármacos , Humanos , Cinesinas/metabolismo , Modelos Biológicos , Modelos Químicos , Nucleotídeos/química , Fenótipo , Ligação Proteica , Tiazóis/farmacologiaRESUMO
Observations from two structurally related series of KSP inhibitors led to the proposal and discovery of dihydropyrazolobenzoxazines that possess ideal properties for cancer drug development. The synthesis and characterization of this class of inhibitors along with relevant pharmacokinetic and in vivo data are presented. The synthesis is highlighted by a key [3+2] cycloaddition to form the pyrazolobenzoxazine core followed by diastereospecific installation of a quaternary center.
Assuntos
Benzoxazinas/química , Benzoxazinas/farmacologia , Desenho de Fármacos , Cinesinas/antagonistas & inibidores , Cinesinas/metabolismo , Mitose/efeitos dos fármacos , Pirazóis/química , Animais , Benzoxazinas/síntese química , Benzoxazinas/farmacocinética , Linhagem Celular , Cães , Humanos , Hidrogênio/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c, exhibited extremely high affinity for the delta opioid receptor with excellent selectivity versus the micro opioid receptor. They were full agonists at the delta opioid receptor, as assessed by stimulation of GTPgammaS binding, and displayed antinociceptive activity.