RESUMO
Control of gonadotropin-releasing hormone (GnRH) signalling is an effective strategy for the treatment of sex hormone-dependent diseases. GnRH analogues have been widely used for treating these diseases; however, initial stimulation or complete suppression of GnRH signalling by GnRH analogues results in the occurrence of several distinct adverse effects. Accordingly, we aimed to discover small molecule GnRH antagonists with superior pharmacokinetic and pharmacodynamic profiles. Linzagolix is a potent, orally available, and selective GnRH antagonist. Here, we reported the pharmacological characterization of linzagolix in vitro and in vivo. Linzagolix selectively binds to the GnRH receptor and inhibits GnRH-stimulated signalling, in a manner comparable to cetrorelix, a peptide GnRH antagonist. Because the inhibitory effect of the gonad axis is useful for the treatment of gynaecological conditions such as endometriosis and uterine fibroids, we investigated the effect of orally administrated linzagolix on the gonadal axis in ovariectomized and intact cynomolgus monkeys. In ovariectomized monkeys, linzagolix immediately suppressed the serum luteinizing hormone concentration at doses over 1 mg/kg, indicating dose-dependent inhibition that correlated with serum linzagolix concentrations. In intact female monkeys, repeated linzagolix administration suppressed hormone surges and ceased or prolonged menstrual cycles. Furthermore, all animals presenting arrested menstrual cycles following linzagolix treatment showed recovery of hormone secretion and regular menstrual cycles after administration periods ended. Our results demonstrated that linzagolix has potential as a novel agent for reproductive-age women suffering from sex hormone-dependent diseases.
Assuntos
Ácidos Carboxílicos , Antagonistas de Hormônios , Hormônio Luteinizante , Pirimidinas , Receptores LHRH , Administração Oral , Animais , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/farmacologia , Feminino , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/farmacologia , Humanos , Hormônio Luteinizante/sangue , Macaca fascicularis , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Receptores LHRH/antagonistas & inibidoresRESUMO
We optimized the structure of an active metabolite (1) of WAY-123783, which was obtained from mouse urine after oral administration, to improve selectivity for SGLT2 and oral bioavailability. O-glucoside derivative 24 (remogliflozin etabonate) was subsequently identified as a potent, highly selective, and orally available SGLT2 inhibitor.
Assuntos
Glucosídeos/química , Glucosídeos/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/química , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Células COS , Chlorocebus aethiops , Descoberta de Drogas , Glicosúria , Camundongos , Estrutura Molecular , Pirazóis/metabolismo , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/metabolismoRESUMO
The production of TrkA-selective inhibitors is considerably difficult because the kinase domains of TrkA and its isoforms TrkB/C have highly homologous amino acid sequences. Here we describe the structural basis for the acquisition of selectivity for a isoform-selective TrkA inhibitor, namely compound V1. The X-ray structure revealed that V1 acts as a molecular glue to stabilize the symmetrical dimer of the TrkA kinase domains. V1 binds to the ATP-binding site and simultaneously engages in the dimeric interface of TrkA. The region of the dimeric interface in TrkA is not conserved in TrkB/C; thus, dimer formation may be a novel mechanism for the production of selective TrkA inhibitors. The biochemical and biophysical assay results confirmed that V1 selectively inhibited TrkA and induced the dimer formation of TrkA, but not TrkB. The binding pocket at the TrkA dimer interface can be used for the production of new isoform-selective TrkA inhibitors.
Assuntos
Isoformas de Proteínas/metabolismo , Receptor trkA/metabolismo , Sequência de Aminoácidos , Humanos , Modelos MolecularesRESUMO
Chronic constipation is a highly common functional gastrointestinal disorder that adversely affects patient quality of life. At present, limited therapeutic options are available for the treatment of chronic constipation, which indicates the need for new therapeutic agents. Herein, we report the potential of mizagliflozin, a novel selective sodium glucose co-transporter 1 (SGLT1) inhibitor, for the amelioration of chronic constipation. Mizagliflozin's inhibitory activity against SGLTs was evaluated by an in vitro assay of cells transiently expressing SGLTs. The safety profile of an initial single dose (2-160mg, orally) and multiple doses (2-20mg, orally, once daily immediately prior to breakfast on Days 1 and 13, and three times daily immediately prior to every meal on Days 3-12) of mizagliflozin was determined by performing a phase I study in healthy male subjects. In addition, the effect of mizagliflozin and lubiprostone on fecal wet weight was compared using a dog model of loperamide-induced constipation and rat model of low-fiber-diet-induced constipation. Mizagliflozin potently inhibited human SGLT1 in a highly selective manner. The results of the phase I study showed mizagliflozin increased stool frequency and loosened stool consistency; these effects increased progressively with an increase in the dosage and the number of doses of mizagliflozin. In addition, the oral administration of mizagliflozin increased fecal wet weight in a dog model of loperamide-induced constipation and a rat model of low-fiber-diet-induced constipation, similar to lubiprostone. These results suggest the potential use of a novel selective SGLT1 inhibitor, mizagliflozin, for the amelioration of chronic constipation.
Assuntos
Amidas/farmacologia , Constipação Intestinal/tratamento farmacológico , Glucosídeos/farmacologia , Pirazóis/farmacologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Amidas/uso terapêutico , Animais , Doença Crônica/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Constipação Intestinal/induzido quimicamente , Fibras na Dieta/farmacologia , Cães , Relação Dose-Resposta a Droga , Glucosídeos/uso terapêutico , Humanos , Loperamida/farmacologia , Masculino , Pirazóis/uso terapêutico , RatosRESUMO
Although numerous crystal structures for protein kinases have been reported, many include only the kinase domain but not the juxtamembrane (JM) region, a critical activity-controlling segment of receptor tyrosine kinases (RTKs). In this study, we determined the X-ray crystal structure of the tropomyosin receptor kinase (Trk) A selective inhibitor A1 complexed with the TrkA kinase domain and the JM region. This structure revealed that the unique inhibitor-binding pocket created by a novel JM configuration yields significant potency and high selectivity against TrkB and TrkC. Moreover, we validated the importance of the JM region for the potency of A1 using in vitro assays. The introduction of moieties that interact with the JM region will be one of the most effective strategies for producing highly selective RTK inhibitors.
Assuntos
Proteínas de Membrana/química , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Receptor trkA/antagonistas & inibidores , Receptor trkA/química , Sítios de Ligação , Bioensaio , Membrana Celular/enzimologia , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Ligação de Hidrogênio , Concentração Inibidora 50 , Proteínas de Membrana/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Receptor trkA/metabolismoRESUMO
The estrogen receptor beta (ERß) selective agonist is considered a promising candidate for the treatment of estrogen deficiency symptoms in ERß-expressing tissues, without the risk of breast cancer, and multiple classes of compounds have been reported as ERß selective agonists. Among them, 6-6 bicyclic ring-containing structures (e.g., isoflavone phytoestrogens) are regarded as one of the cyclized analogues of isobutestrol 5b, and suggest that other cyclized scaffolds comprising 5-6 bicyclic rings could also act as selective ERß ligands. In this study, we evaluated the selective ERß agonistic activity of 1-(4-hydroxybenzyl)indan-5-ol 7a and studied structure-activity relationship (SAR) of its derivatives. Some functional groups improved the properties of 7a; introduction of a nitrile group on the indane-1-position resulted in higher selectivity for ERß (12a), and further substitution with a fluoro or a methyl group to the pendant phenyl ring was also preferable (12b, d, and e). Subsequent chiral resolution of 12a identified that R-12a has a superior profile over S-12a. This is comparable to diarylpropionitrile (DPN) 5c, one of the promising selective ERß agonists and indicates that this indane-based scaffold has the potential to provide better ERß agonistic probes.
Assuntos
Receptor beta de Estrogênio/agonistas , Indanos/farmacologia , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Células HEK293 , Humanos , Indanos/síntese química , Indanos/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a). To further improve SGLT1 inhibitory activity and reduce aglycone permeability, a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl ß-D-glycopyranoside derivatives bearing novel hydrophilic substitution groups on the phenyl ring were synthesized and their inhibitory activity toward SGLTs was evaluated. Optimized compound 14c showed an improved profile satisfying both higher activity and lower permeability of its aglycone (22f) compared with initial leads 1 and 2. Moreover, the superior efficacy of 14c in various carbohydrate tolerance tests in diabetic rat models was confirmed compared with acarbose, an α-glucosidase inhibitor (α-GI) widely used in the clinic.
Assuntos
Desenho de Fármacos , Glicosídeos/farmacologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Relação Dose-Resposta a Droga , Glicosídeos/síntese química , Glicosídeos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl ß-d-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors. Representative derivatives showed a dose-dependent suppressing effect on the escalation of blood glucose levels in oral mixed carbohydrate tolerance tests (OCTT) in streptozotocin-nicotinamide-induced diabetic rats (NA-STZ rats).
Assuntos
Glucosídeos/química , Hipoglicemiantes/síntese química , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Animais , Glicemia/análise , Cristalografia por Raios X , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/síntese química , Glucosídeos/uso terapêutico , Humanos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Conformação Molecular , Ratos , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose , Relação Estrutura-AtividadeRESUMO
The high-affinity sodium glucose cotransporter (SGLT1) plays a critical role in glucose absorption from the gastrointestinal tract. We have developed 3-(3-{4-[3-(ß-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide (KGA-2727), which has a pyrazole-O-glucoside structure, as the first selective SGLT1 inhibitor. KGA-2727 inhibited SGLT1 potently and highly selectively in an in vitro assay using cells transiently expressing recombinant SGLTs. In a small intestine closed loop absorption test with normal rats, KGA-2727 inhibited the absorption of glucose but not that of fructose. After oral intake of starch along with KGA-2727 in normal rats, the residual content of glucose in the gastrointestinal tract increased. In the oral glucose tolerance test with streptozotocin-induced diabetic rats, KGA-2727 attenuated the elevation of plasma glucose after glucose loading, indicating that KGA-2727 improved postprandial hyperglycemia. In Zucker diabetic fatty (ZDF) rats, chronic treatments with KGA-2727 reduced the levels of plasma glucose and glycated hemoglobin. Furthermore, KGA-2727 preserved glucose-stimulated insulin secretion and reduced urinary glucose excretion with improved morphological changes of pancreatic islets and renal distal tubules in ZDF rats. In addition, the chronic treatment with KGA-2727 increased the level of glucagon-like peptide-1 in the portal vein. Taken together, our data indicate that the selective SGLT1 inhibitor KGA-2727 had antidiabetic efficacy and allow us to propose KGA-2727 as a candidate for a novel and useful antidiabetic agent.