RESUMO
There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 µM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 µM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.
Assuntos
Vírus BK/enzimologia , DNA Helicases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Vírus JC/enzimologia , DNA Helicases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The bioisosteric replacement of the indole core of CRTH2 antagonists using thienopyrroles was investigated, resulting in potent antagonists with good selectivity over DP1. Early ADME/PK assessment of this chemotype demonstrated bioavailability in mice.
Assuntos
Acetatos/farmacologia , Pirróis/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/química , Acetatos/farmacocinética , Animais , Disponibilidade Biológica , Camundongos , Microssomos Hepáticos/metabolismo , RatosRESUMO
Series of aminopyridinecarboxamide-based inhibitors were synthesized and tested against human recombinant IKK-2 and in IL-1beta stimulated synovial fibroblasts. The 2-amino-5-chloropyridine-4-carboxamides were identified as the most potent inhibitors with improved cellular activity.
Assuntos
Aminopirina/química , Aminopirina/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Interleucina-1beta/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Sequência de Aminoácidos , Artrite Reumatoide/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Humanos , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/química , Interleucina-1beta/metabolismo , Cápsula Articular/citologia , Dados de Sequência Molecular , Relação Estrutura-AtividadeRESUMO
BACKGROUND: TGF-beta has been identified as a key factor in the progression of various diseases, in particular cancer and fibrosis. The signaling of TGF-beta can be modulated through three distinct strategies: using antisense nucleotides that block TGF-beta mRNA (trabedersen (AP 12009)), using monoclonal antibodies to block TGF-beta isoforms (lerdelimumab, metelimumab) or using small molecule inhibitors of the TGF-beta receptor 1 (TGF-betaR1 or ALK-5). OBJECTIVE: This review focuses on small molecules and summarizes the most recent TGF-betaR1 inhibitors reported in the patent literature. METHODS: We searched and analyzed the patent literature claiming chemical matter for TGF-betaR1 inhibition from the 1(st) of January 2005 to the 1(st) of January 2009. RESULTS/CONCLUSIONS: The inhibition of TGF-beta has recently been clinically validated with antisense nucleotide trabedersen. Small molecules inhibitors of TGF-betaR1 that are now in Phase I clinical trials and in preclinical stage are, therefore, of high interest and could provide a more versatile route to TGF-beta modulation through oral dosing while maintaining the same therapeutic benefits.
Assuntos
Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Fibrose/tratamento farmacológico , Fibrose/fisiopatologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Patentes como Assunto , Receptor do Fator de Crescimento Transformador beta Tipo I , Transdução de Sinais/efeitos dos fármacosRESUMO
The 4-(5-fluoro-6-methyl-pyridin-2-yl)-5-quinoxalin-6-yl-1H-imidazol-2-ylamine 3 is a potent and selective inhibitor of TGF-betaR1. Substitution of the amino group of 3 typically led to a slight decrease in the affinity for the receptor and in TGF-beta-inducted PAI-luciferase reporter activity. However, 2-acetamidoimidazoles were identified as attractive candidates for further optimization as a result of their significant activity combined to their superior pharmacokinetic profile.
Assuntos
Química Farmacêutica/métodos , Imidazóis/síntese química , Imidazóis/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Luciferases/metabolismo , Masculino , Modelos Biológicos , Conformação Molecular , Ratos , Ratos Sprague-DawleyRESUMO
A series of 21 novel 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides were synthesized and evaluated for the inhibition of IKK-2. In spite of their often modest activity on the enzyme, six selected analogs showed significant inhibition of the production of inflammatory cytokine IL-8 in IL-1beta stimulated rheumatoid arthritis-derived synovial fibroblasts, demonstrating their potential usefulness as NF-kappaB regulators.