RESUMO
The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ~10nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization.
Assuntos
MAP Quinase Quinase Quinases/antagonistas & inibidores , Piridinas , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Animais , Cristalografia por Raios X , Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Structure-guided design led to the discovery of novel chemical scaffolds for B-Raf inhibitors. Both type I and type II kinase inhibitors have been explored and lead compounds with good potency and excellent selectivity have been identified.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Isoindóis/síntese química , Ftalazinas/síntese química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Benzenossulfonatos/química , Benzenossulfonatos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Isoindóis/química , Isoindóis/farmacologia , Modelos Moleculares , Estrutura Molecular , Niacinamida/análogos & derivados , Compostos de Fenilureia , Ftalazinas/química , Ftalazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Sorafenibe , Relação Estrutura-AtividadeRESUMO
Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models.
Assuntos
Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Indazóis/síntese química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/síntese química , Pirimidinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/química , Indazóis/farmacologia , Camundongos , Modelos Moleculares , Mutação , Transplante de Neoplasias , Proteínas Proto-Oncogênicas B-raf/genética , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
A series of tricyclic anilinopyrimidines were synthesized and evaluated as IKKbeta inhibitors. Several analogues, including tricyclic phenyl (10, 18a, 18c, 18d, and 18j) and thienyl (26 and 28) derivatives were shown to have good in vitro enzyme potency and excellent cellular activity. Pharmaceutical profiling of a select group of tricyclic compounds compared to the non-tricyclic analogues suggested that in some cases, the improved cellular activity may be due to increased clog P and permeability.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Linhagem Celular , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Relação Estrutura-AtividadeRESUMO
It was found that solvent hydrogen bond basicity (SHBB) significantly affects the regiochemistry of the S(N)Ar reaction between secondary amines and activated polyfluoroarenes. A plausible mechanism involving a six-membered transition state is invoked for the formation of an ortho-substituted isomer, which is likely organized by a hydrogen bond. Evidence for this hypothesis is presented, and a regioselective amination reaction of activated polyfluoroarenes has been developed.
Assuntos
Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/síntese química , Ligação de Hidrogênio , Estrutura Molecular , Solventes/química , EstereoisomerismoRESUMO
As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.
Assuntos
Benzamidas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Benzamidas/síntese química , Benzamidas/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.
Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/química , Piridinas/química , Pirimidinas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Pirazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologiaRESUMO
A series of pyrazolo[1,5-alpha]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Insulin-like growth factor receptor (IGF-1R) is a growth factor receptor tyrosine kinase that acts as a critical mediator of cell proliferation and survival. Inhibitors of this receptor are believed to provide a new target in cancer therapy. We previously reported an isoquinolinedione series of IGF-1R inhibitors. Now we have identified a series of 3-cyanoquinoline compounds that are low nanomolar inhibitors of IGF-1R. The strategies, synthesis, and SAR behind the cyanoquinoline scaffold will be discussed.
Assuntos
Antineoplásicos/síntese química , Nitrilas/síntese química , Quinolinas/síntese química , Receptor IGF Tipo 1/antagonistas & inibidores , Humanos , Nitrilas/farmacologia , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of substituted 7-alkenyl 4[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-3-quinolinecarbonitrile analogs were synthesized and evaluated as MEK1 kinase inhibitors. The synthetic details, structure-activity relationships, biological activity, and selected oral exposure studies of these analogs are described. From these studies, compound 5m was chosen as a strong candidate for further evaluation. The selectivity of 5m was ascertained against a panel of 17 kinases, where activity was observed against EGFR, Src, Lyn, and IR kinases. Western blot studies in WM-266 cells demonstrated that 5m inhibited phosphorylation of ERK, while additional kinase pathways tested showed no inhibition at up to 10 microM of 5 m. PK studies, as well as a xenograft and in vivo biomarker studies are described for 5m.
Assuntos
Alcenos/química , Compostos de Anilina/química , MAP Quinase Quinase 1/antagonistas & inibidores , Nitrilas/síntese química , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Isoquinolinas/química , MAP Quinase Quinase 1/metabolismo , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias/enzimologia , Nitrilas/química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Especificidade por Substrato , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
It has been previously reported that appropriately substituted 4-anilinoquinoline-3-carbonitriles are potent inhibitors of Src kinase, with biological activity in vitro and in vivo. Structural modifications to these compounds have been explored, providing the 4-anilinobenzo[g]quinoline-3-carbonitriles as a series with enhanced Src inhibitory properties. The synthesis and structure-activity relationships of these 4-anilino-7,8-dialkoxybenzo[g]quinoline-3-carbonitriles are presented here. Analogues with cyclic basic amine groups attached via ethoxy linkages at the C-8 position were the most active in vitro, with subnanomolar IC50 values against Src kinase observed for a majority of the compounds synthesized. Compound 17d was more potent in vitro than the analogously substituted 4-anilinoquinoline-3-carbonitrile SKI-606, which is undergoing evaluation in clinical trials. The most potent analogue synthesized was 17a, with an IC50 of 0.15 nM against Src kinase and with an IC50 of 10 nM against Src-transformed fibroblasts. Molecular modeling studies provided a rationale for the exceptional activity observed for these compounds, with favorable van der Waals interactions playing the major role. Compound 17c was found to be highly selective for Src kinase when tested against a panel of other kinases, with modest selectivity versus the Src family kinases Lyn and Fyn. Following ip dosing at 50 mg/kg, analogues 17c and 17d were shown to have plasma levels that significantly exceeded the cellular IC50 values against Src-transformed fibroblasts. In an Src-transformed fibroblast xenograft model, both compounds exhibited a significant inhibition of tumor growth.