RESUMEN
Transient receptor potential cation channel subfamily M member 5 (TRPM5) is a nonselective monovalent cation channel activated by intracellular Ca2+ increase. Within the gastrointestinal system, TRPM5 is expressed in the stoma, small intestine, and colon. In the search for a selective agonist of TRPM5 possessing in vivo gastrointestinal prokinetic activity, a high-throughput screening was performed and compound 1 was identified as a promising hit. Hit validation and hit to lead activities led to the discovery of a series of benzo[d]isothiazole derivatives. Among these, compounds 61 and 64 showed nanomolar activity and excellent selectivity (>100-fold) versus related cation channels. The in vivo drug metabolism and pharmacokinetic profile of compound 64 was found to be ideal for a compound acting locally at the intestinal level, with minimal absorption into systemic circulation. Compound 64 was tested in vivo in a mouse motility assay at 100 mg/kg, and demonstrated increased prokinetic activity.
Asunto(s)
Benzotiazoles/química , Benzotiazoles/farmacología , Tracto Gastrointestinal/metabolismo , Ensayos Analíticos de Alto Rendimiento , Canales Catiónicos TRPM/agonistas , Animales , Benzotiazoles/metabolismo , Benzotiazoles/farmacocinética , Diseño de Fármacos , Tracto Gastrointestinal/efectos de los fármacos , Humanos , Masculino , Ratones , Terapia Molecular Dirigida , Reproducibilidad de los Resultados , Distribución TisularRESUMEN
Cystic fibrosis (CF) is a multiorgan disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses and bacteria trigger acute pulmonary exacerbations, accelerating disease progression and mortality rate. Treatment complexity increases with patients' age, and simplifying the therapeutic regimen represents one of the key priorities in CF. We have recently reported the discovery of multitarget compounds able to "kill two birds with one stone" by targeting F508del-CFTR and PI4KIIIß and thus acting simultaneously as CFTR correctors and broad-spectrum enterovirus (EV) inhibitors. Starting from these preliminary results, we report herein a hit-to-lead optimization and multidimensional structure-activity relationship (SAR) study that led to compound 23a. This compound showed good antiviral and F508del-CFTR correction potency, additivity/synergy with lumacaftor, and a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. It was well tolerated in vivo with no sign of acute toxicity and histological alterations in key biodistribution organs.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Fibrosis Quística/tratamiento farmacológico , Microsomas Hepáticos/efectos de los fármacos , Animales , Antivirales , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Humanos , Masculino , Membranas Artificiales , Ratones , Ratones Endogámicos C57BL , Permeabilidad , Unión Proteica , Albúmina Sérica Humana/química , Albúmina Sérica Humana/metabolismo , Pruebas de ToxicidadRESUMEN
Together with estrogen receptors ERα and ERß, the Gâ protein-coupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative (ER-) and triple-negative (TN) breast cancer. Only a few selective GPER modulators have been reported to date, and their use in cancer cell lines has often led to contradictory results. Herein we report the application of virtual screening and cell-based studies for the identification of new chemical scaffolds with a specific antiproliferative effect against GPER-expressing breast cancer cell lines. Out of the four different scaffolds identified, 8-chloro-4-(4-chlorophenyl)pyrrolo[1,2-a]quinoxaline 14 c was found to be the most promising compound able to induce: 1)â antiproliferative activity in GPER-expressing cell lines (MCF7 and SKBR3), similarly to G15; 2)â no effect on cells that do not express GPER (HEK293); 3)â a decrease in cyclinâ D1 expression; and 4)â a sustained induction of cell-cycle negative regulators p53 and p21.
Asunto(s)
Antineoplásicos/metabolismo , Quinoxalinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclina D1/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/antagonistas & inhibidores , Receptor beta de Estrógeno/metabolismo , Femenino , Células HEK293 , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Quinoxalinas/química , Quinoxalinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Enteroviruses (EVs) are among the most frequent infectious agents in humans worldwide and represent the leading cause of upper respiratory tract infections. No drugs for the treatment of EV infections are currently available. Recent studies have also linked EV infection with pulmonary exacerbations, especially in cystic fibrosis (CF) patients, and the importance of this link is probably underestimated. The aim of this work was to develop a new class of multitarget agents active both as broad-spectrum antivirals and as correctors of the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding defect responsible for >90% of CF cases. We report herein the discovery of the first small molecules able to simultaneously act as correctors of the F508del-CFTR folding defect and as broad-spectrum antivirals against a panel of EVs representative of all major species.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/virología , Enterovirus/efectos de los fármacos , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/química , Descubrimiento de Drogas , Infecciones por Enterovirus/tratamiento farmacológico , Infecciones por Enterovirus/genética , Infecciones por Enterovirus/virología , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Mutación , Pliegue de Proteína/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Oxazoles/farmacología , Apoptosis/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Células K562 , Ligandos , Estructura Molecular , Receptores Adrenérgicos alfa 2/efectos de los fármacos , RilmenidinaRESUMEN
INTRODUCTION: Maraviroc is a first-in-class antiretroviral (ARV) drug acting on a host cell target (CCR5), which blocks the entry of the HIV virus into the cell. Maraviroc is currently indicated for combination ARV treatment in adults infected only with CCR5-tropic HIV-1. AREAS COVERED: This drug discovery case history focuses on the key studies that led to the discovery and approval of maraviroc, as well as on post-launch clinical reports. The article is based on the data reported in published preclinical and clinical studies, conference posters and on drug package data. EXPERT OPINION: The profound understanding of HIV's entry mechanisms has provided a strong biological rationale for targeting the chemokine receptor CCR5. The CCR5-antagonist mariviroc, with its unique mode of action and excellent safety profile, is an important therapeutic option for HIV patients. In general, the authors believe that targeting host factors is a useful approach for combating new and re-emerging transmissible diseases, as well as pathogens that easily become resistant to common antiviral drugs. Maraviroc, offering a potent and safe cellular receptor-mediated pharmacological response to HIV, has paved the way for the development of a new generation of host-targeting antivirals.