RESUMEN
While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the 'immune fingerprint' of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Sistema Inmunológico/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Quimiocinas/biosíntesis , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Fagocitos/efectos de los fármacos , Fagocitos/inmunología , Fagocitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Receptores Toll-Like/metabolismo , Transcriptoma/efectos de los fármacosRESUMEN
In a search for novel small molecule calcium-sensing receptor (CaSR) antagonists as oral bone anabolic agents, we discovered dihydrobenzofuran cyclopropane carboxylic acid derivatives, such as 12f (IC50=27.6nM), are highly potent calcium-sensing receptor antagonists. Studies in rats established that compound 12f stimulates parathyroid hormone (PTH) release in a fast-acting, pulsatile manner.
Asunto(s)
Benzofuranos/química , Ciclopropanos/metabolismo , Osteoporosis/tratamiento farmacológico , Receptores Sensibles al Calcio/antagonistas & inhibidores , Administración Oral , Animales , Benzofuranos/metabolismo , Benzofuranos/farmacocinética , Benzofuranos/uso terapéutico , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapéutico , Evaluación Preclínica de Medicamentos , Femenino , Semivida , Osteoporosis/patología , Hormona Paratiroidea/sangre , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Sensibles al Calcio/metabolismo , Relación Estructura-ActividadAsunto(s)
Artritis/inmunología , Indazoles/farmacología , Enfermedades Inflamatorias del Intestino/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Células Th17/efectos de los fármacos , Células Th17/inmunología , Artritis/tratamiento farmacológico , Artritis/genética , Artritis/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Indazoles/química , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Interleucina-17/biosíntesis , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/metabolismoRESUMEN
A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies.