RESUMEN
The progesterone receptor (PR) is a ligand-activated steroid receptor in the nuclear receptor (NR) superfamily of transcription factor. Besides gynecological and obstetrical indications, the involvement/mechanism of PR in many other diseases, such as oncology, neurology, immunology, etc. has been revealed and studied in recent decades. Therapeutic agents that selectively activate or inhibit PR have been developed. PR agonists have generally been used in oral contraception and postmenopausal hormone replacement therapy (HRT), typically in combination with estrogens. PR antagonists and selective PR modulators (SPRMs) can be useful therapies for hormone dependent breast and prostate cancers, nonmalignant chronic conditions such as fibroids, and endometriosis. This review provides an overview and detailed discussions about the recent development of chemical structures of the PR ligands, their structural characteristics (particularly those contributing to their activity and selectivity), in vitro/in vivo studies and clinical trial outcomes, and the synthetic methodologies.
Asunto(s)
Ligandos , Receptores de Progesterona/metabolismo , Boranos/síntesis química , Boranos/química , Boranos/metabolismo , Cumarinas/síntesis química , Cumarinas/química , Cumarinas/metabolismo , Compuestos Heterocíclicos de Anillos Fusionados/síntesis química , Compuestos Heterocíclicos de Anillos Fusionados/química , Compuestos Heterocíclicos de Anillos Fusionados/metabolismo , Terapia de Reemplazo de Hormonas , Humanos , Hidrocarburos Alicíclicos/síntesis química , Hidrocarburos Alicíclicos/química , Hidrocarburos Alicíclicos/metabolismo , Indoles/síntesis química , Indoles/química , Indoles/metabolismo , Unión Proteica , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inhibidores , Esteroides/síntesis química , Esteroides/química , Esteroides/metabolismo , Vitamina D/análogos & derivados , Vitamina D/síntesis química , Vitamina D/metabolismoRESUMEN
Preclinical studies for neurodegenerative diseases have shown a multi-targeted approach to be successful in the treatment of these complex disorders with several pathoetiological pathways. Polycyclic compounds, such as NGP1-01 (7a), have demonstrated the ability to target multiple mechanisms of the complex etiology and are referred to as multifunctional compounds. These compounds have served as scaffolds with the ability to attenuate Ca(2+) overload and excitotoxicity through several pathways. In this study, our focus was on mitigating Ca(2+) overload through the L-type calcium channels (LTCC). Here, we report the synthesis and biological evaluation of several novel polycyclic compounds. We determined the IC50 values for both the pentacycloundecylamines and the triquinylamines by means of a high-throughput fluorescence calcium flux assay utilizing Fura-2/AM. The potential of these compounds to offer protection against hydrogen peroxide-induced cell death was also evaluated. Overall, 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6) .0(3,10) .0(5,9) ]undecane (NGP1-01, 7a) had the most favorable pharmacological profile with an IC50 value of 86 µM for LTCC inhibition and significant reduction of hydrogen peroxide-induced cell death. In general, the triquinylamines were more active as LTCC blockers than the oxa-pentacycloundecylamines. The aza-pentacycloundecylamines were potent LTCC inhibitors, with 8-hydroxy-N-phenylethyl-8,11-azapentacyclo[5.4.0.0(2,6) .0(3,10) .0(5,9) ]undecane (8b) also able to offer significant protection in the cell viability assays.