RESUMO
Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.
Assuntos
Benzimidazóis/farmacologia , Receptores Opioides kappa/agonistas , Sequência de Aminoácidos , Simulação por Computador , Humanos , Dados de Sequência Molecular , Receptores Opioides kappa/química , Homologia de Sequência de Aminoácidos , Relação Estrutura-AtividadeRESUMO
We describe the synthesis and characterization of 3-alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor (AR) modulators that possess excellent physicochemical properties for transdermal administration. Compound 26 bound to human AR with an IC50 of 0.7 nM with great selectivity over other nuclear hormone receptors and potently activated AR in a C2C12 muscle cell reporter gene assay with an EC50 of 0.5 nM. It showed high aqueous solubility of 1.3 g/L at pH 7.4, and an in silico model as well as a customized parallel artificial membrane permeability assay indicated good skin permeation. Indeed, when measuring skin permeation through excised human skin, an excellent flux of 2 µg/(cm(2)·h) was determined without any permeation enhancers. In a 2 week Hershberger model using castrated rats, the compound showed dose-dependent effects fully restoring skeletal muscle weight at 0.3 mg/kg/day after subcutaneous administration with high selectivity over prostate stimulation.
Assuntos
Antagonistas de Receptores de Andrógenos/química , Androgênios/química , Compostos Azabicíclicos/química , Pirazóis/química , Receptores Androgênicos/química , Administração Cutânea , Antagonistas de Receptores de Andrógenos/metabolismo , Antagonistas de Receptores de Andrógenos/farmacocinética , Androgênios/metabolismo , Animais , Área Sob a Curva , Compostos Azabicíclicos/metabolismo , Compostos Azabicíclicos/farmacocinética , Sítios de Ligação , Ligação Competitiva , Linhagem Celular , Fenômenos Químicos , Cristalografia por Raios X , Humanos , Masculino , Taxa de Depuração Metabólica , Camundongos , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Estrutura Terciária de Proteína , Pirazóis/metabolismo , Pirazóis/farmacocinética , Ratos Wistar , Receptores Androgênicos/metabolismo , Pele/metabolismoRESUMO
Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.
