RESUMO
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Assuntos
Inibidores Enzimáticos/farmacologia , Iminas/farmacologia , Pirimidinonas/farmacologia , Renina/antagonistas & inibidores , Administração Oral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Iminas/síntese química , Iminas/química , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/química , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.
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
BACKGROUND: Years of political instability, civil unrest, and disease have left scores of Ugandans in need of mental health services. However, there are few formal mental health services available in the country. Professional helpers such as clergy, teachers, and healthcare workers who have strong ties to their communities are frequently placed in formal counseling roles. AIMS: To develop, implement, and evaluate a training model for developing micro-counseling skills designed specifically for informal helpers in Uganda. METHODS: Forty-four professional helpers were provided with a one-week, 40-hour training program in microcounseling skills. RESULTS: Following the training program, trainees demonstrated proficiency in basic counseling skills and attained an increased knowledge of those skills. CONCLUSIONS: This training was readily assimilated and supported the ecological validity of the microcounseling model.