RESUMO
A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. .
Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Fenilenodiaminas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Microssomos Hepáticos/metabolismo , Fenilenodiaminas/síntese química , Fenilenodiaminas/química , Fenilenodiaminas/metabolismo , Relação Estrutura-AtividadeRESUMO
This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing.
Assuntos
Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Naftalenossulfonatos/química , Naftalenossulfonatos/farmacologia , Administração Oral , Antagonistas de Receptores de Andrógenos/farmacocinética , Animais , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/farmacocinética , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Naftalenossulfonatos/administração & dosagem , Naftalenossulfonatos/farmacocinética , Ratos , Receptores Androgênicos/metabolismo , Relação Estrutura-AtividadeRESUMO
BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.
RESUMO
A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo.
Assuntos
Antineoplásicos/síntese química , Nitrilas/química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Masculino , Nitrilas/síntese química , Nitrilas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Relação Estrutura-AtividadeRESUMO
Allyl(crotyl)enolsilanes, when constrained in a five-membered ring with a 1,2-diol, react with aldehydes in a tandem aldol-allylation reaction to give polyketide fragments. These experimentally trivial and efficient reactions establish two new carbon-carbon bonds and up to four new stereocenters. The silane reagents, which owe their reactivity to strain release Lewis acidity, are easily prepared and stable to storage.