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1.
Drug Des Devel Ther ; 13: 817-824, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880915

RESUMO

Gene knockout has been a powerful technique to evaluate the physiologic role of selected gene products. Lexicon pioneered high-throughput gene knockout technology and went further in designing agents to inhibit products of gene expression. Two agents have entered late-stage development. Telotristat is an inhibitor of tryptophan hydroxylase (TPH), preventing the production of serotonin. Although this agent blocks the two isoforms of TPH, it does not cross the blood-brain barrier, thus avoiding central neurologic manifestations. It inhibits the peripheral production of serotonin, and in particular prevents serotonin action in the intestines, resulting in decreased peristaltic action. Lexicon successfully developed telotristat to treat carcinoid syndrome not responding adequately to somatostatin inhibitors. Sotagliflozin development proceeded from the observation that dual inhibition of SGLT2 in the kidneys and SGLT1 in the intestines resulted in increased renal glucose excretion, reduced early-phase glucose absorption, as well as increased blood levels of GLP-1 and PYY. Initial development efforts focused on type 1 diabetes and have shown reduced postprandial glucose levels, less tendency to hypoglycemia, and lower HbA1c. Several other SGLT2 inhibitors have been associated with increased frequency of diabetic ketoacidosis (DKA). In the type 1 trials, sotagliflozin-treated individuals experienced DKA at a higher rate than placebo-treated patients. The sotagliflozin development program has now been extended to trials on type 2 diabetes. Long-term clinical trials will determine the benefits and risks of the agent in comparison to other currently marketed SGLT2 inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Técnicas de Inativação de Genes , Glicosídeos/farmacologia , Hipoglicemiantes/farmacologia , Fenilalanina/análogos & derivados , Pirimidinas/farmacologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Transportador 2 de Glucose-Sódio/metabolismo , Triptofano Hidroxilase/antagonistas & inibidores , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Humanos , Fenilalanina/farmacologia , Serotonina/biossíntese , Serotonina/metabolismo , Transportador 1 de Glucose-Sódio/genética , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/genética , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
2.
Clin Ther ; 40(12): 2006-2020.e2, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30477789

RESUMO

PURPOSE: Patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS) may experience chronic, recurring symptoms despite somatostatin analogue therapy. Little is known about the relationship between bowel movement (BM) frequency, patient-reported symptoms and health-related quality of life (QoL). Data from the TELESTAR study were used in exploratory, post hoc analyses to understand the relationship between durable reductions in BM frequency, symptom relief, and health-related QoL. METHODS: Patients with metastatic neuroendocrine tumors and CS in the Phase III TELESTAR study were randomized (1:1:1) to receive telotristat ethyl (TE) 250 mg, TE 500 mg, or placebo three times daily (TID) during a 12-week double-blind treatment period (DBTP). All patients received TE 500 mg TID in an open-label extension (OLE) to Week 48. Durable response was predefined. Analyses compared durable responders (DRs) and non-durable responders (NDRs), irrespective of treatment group, at Weeks 12, 24, and 48. FINDINGS: At the start of the DBTP, 135 patients were randomized, 45 patients each to TE 250 mg, TE 500 mg, and placebo. After the 12-week DBTP, 48 of 135 patients were DRs (TE 250 mg, n = 20; TE 500 mg, n = 19; placebo, n = 9). Of the 115 patients who entered the OLE, 35 were DRs initially randomized to TE 250 mg (n = 18) or 500 mg (n = 17), 29 of whom maintained a durable response throughout the OLE. Of the 71 DBTP-NDRs (inclusive of patients initially randomized to placebo), 28 became OLE-DRs. There were 29 NDRs initially randomized to placebo who entered the OLE, 16 of whom became DRs when switched to TE 500 mg. DRs during the DBTP had greater symptom improvements in the DBTP; these improvements continued over the OLE. DBTP-DRs also maintained more meaningful QoL improvements in EORTC QLQ-C30 global health status, nausea and vomiting, pain, diarrhea, and EORTC QLQ-GINET21 gastrointestinal symptoms over the DBTP and OLE periods than DBTP-NDRs. IMPLICATIONS: These results suggest that sustained improvements in BM frequency in patients with CS may have multifaceted, long-term effects on a patient's well-being. ClinicalTrials.gov identifiers: NCT01677910.


Assuntos
Diarreia/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Fenilalanina/uso terapêutico , Qualidade de Vida , Resultado do Tratamento , Triptofano Hidroxilase/antagonistas & inibidores
3.
Am J Physiol Endocrinol Metab ; 315(6): E1133-E1142, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30351987

RESUMO

Long-term effects of breastfeeding on maternal bone are not fully understood. Excessive maternal bone loss stimulated by serotonin signaling during lactation may increase bone fragility later in life. We hypothesized that inhibiting nonneuronal serotonin activity by feeding a small-molecule inhibitor of the rate-limiting enzyme in serotonin synthesis [tryptophan hydroxylase 1 (TPH1)] would preserve maternal bone postweaning without affecting neonatal bone. Chow supplemented with the small-molecule TPH1 inhibitor LP778902 (~100 mg/kg) or control chow was fed to C57BL/6 dams throughout pregnancy and lactation, and blood was collected on days 1 and 21 of lactation. Dams returned to a common diet postweaning and were aged to 3 or 9 mo postweaning. Pups were euthanized at weaning. The effect of TPH1 inhibition on dam and pup femoral bone was determined by micro-computed tomography. Peripartum dietary supplementation with LP778902 decreased maternal serum serotonin concentrations ( P = 0.0007) and reduced bone turnover, indicated by serum NH2-terminal propeptide of type I collagen ( P = 0.01) and COOH-terminal collagen cross-links ( P = 0.02) concentrations, on day 21 of lactation. Repressed bone turnover from TPH1 inhibition was not associated with structural changes in maternal femur at 3 or 9 mo postweaning. By contrast, neonates exposed to peripartum LP778902 demonstrated differences in trabecular and cortical femoral bone compared with pups from control dams, with fewer ( P = 0.02) and thinner ( P = 0.001) trabeculae as well as increased trabecular spacing ( P = 0.04). Additionally, cortical porosity was increased ( P = 0.007) and cortical tissue mineral density was decreased ( P = 0.005) in pups of LP778902-treated dams. Small-molecule TPH1 inhibitors should be carefully considered in pregnant and lactating women, given potential risks to neonatal bone development.


Assuntos
Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Fêmur/diagnóstico por imagem , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Serotonina/sangue , Triptofano Hidroxilase/antagonistas & inibidores , Animais , Biomarcadores/sangue , Colágeno Tipo I/sangue , Suplementos Nutricionais , Feminino , Lactação/efeitos dos fármacos , Camundongos , Peptídeos/sangue , Gravidez , Microtomografia por Raio-X
4.
Cell Physiol Biochem ; 48(6): 2409-2428, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30121645

RESUMO

BACKGROUND/AIMS: Previously, we confirmed that liver-synthesized 5-HT rather than non-liver 5-HT, acting on the 5-HT2 receptor (5-HT2R), modulates lipid-induced excessive lipid synthesis (ELS). Here, we further revealed the effects of the hepatocellular 5-HT system in diabetes-related disorders. METHODS: Studies were conducted in male ICR mice, human HepG2 cells, and primary mouse hepatocytes (PMHs) under gene or chemical inhibition of the 5-HT system, key lipid metabolism, and inflammation-related factors. Protein and messenger RNA expression and levels of the factors were determined via western blotting, reverse transcription PCR, and quantitative assay kits, respectively. Hepatic steatosis with inflammation and fibrosis, intracellular lipid droplet accumulation (LDA), and reactive oxygen species (ROS) location were determined via hematoxylin and eosin, Masson's trichrome, Oil red O, and fluorescent-specific staining, respectively. RESULTS: Palmitic acid induced the activation of the 5-HT system: the activation of 5-HT2R, primarily 5-HT2AR, in addition to upregulating monoamine oxidase A (MAO-A) expression and 5-HT synthesis, by activating the G protein/ phospholipase C pathway modulated PKCε activation, resulting in ELS with LDA; the activation of NF-κB, which mediates the generation of pro-inflammatory cytokines, was primarily due to ROS generation in the mitochondria induced by MAO-A-catalyzed 5-HT degradation, and secondarily due to the activation of PKCε. These effects of the 5-HT system were also detected in palmitic acid- or high glucose-treated PMHs and regulated multiple inflammatory signaling pathways. In diabetic mice, co-treatment with antagonists of both 5-HT synthesis and 5-HT2R significantly abolished hepatic steatosis, inflammation, and fibrosis as well as hyperglycemia and dyslipidemia. CONCLUSION: Activation of the hepatocellular 5-HT system plays a crucial role in inducing diabetes-related hepatic dysfunction and is a potential therapeutic target.


Assuntos
Citocinas/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/antagonistas & inibidores , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Células Hep G2 , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Monoaminoxidase/química , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Ácido Palmítico/farmacologia , Proteína Quinase C-épsilon/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores 5-HT2 de Serotonina/química , Receptores 5-HT2 de Serotonina/genética , Serotonina/farmacologia , Triptofano Hidroxilase/antagonistas & inibidores , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
5.
Drugs ; 78(9): 941-950, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29931594

RESUMO

Telotristat ethyl (Xermelo®), a first-in-class peripheral tryptophan hydroxylase (TPH) inhibitor, is approved to treat carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy alone. Some neuroendocrine tumours secrete serotonin (5-HT) into the blood, resulting in frequent bowel movements (BMs) and other symptoms. Telotristat ethyl inhibits TPH, thereby reducing the production of 5-HT and improving carcinoid syndrome diarrhoea. In the 12-week placebo-controlled phase of randomized trials in patients with carcinoid syndrome diarrhoea (most of whom were receiving SSA therapy), the addition of oral telotristat ethyl 250 three times daily provided significant reductions in the frequency of BMs and levels of urinary 5-hydroxyindolacetic acid (u5-HIAA; a metabolite of 5-HT) relative to placebo. Telotristat ethyl 250 mg three times daily was well tolerated, with the proportion of patients reporting at least one treatment-emergent adverse event being similar to that with placebo. With regard to adverse events of special interest, relative to placebo, telotristat ethyl had a comparable incidence of depression-related symptoms, a somewhat higher incidence of gastrointestinal (GI) disorders and a higher incidence of elevated hepatic enzyme levels.


Assuntos
Diarreia/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Triptofano Hidroxilase/antagonistas & inibidores , Interações de Medicamentos , Quimioterapia Combinada , Humanos , Fenilalanina/administração & dosagem , Fenilalanina/efeitos adversos , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Resultado do Tratamento
6.
Clin Ther ; 40(6): 952-962.e2, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29724499

RESUMO

PURPOSE: In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m2) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival. METHODS: Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan. FINDINGS: In 120 patients with weight data available, weight gain ≥3% was observed in 2 of 39 patients (5.1%) taking placebo TID, 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss ≥3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status. IMPLICATIONS: Up to 32.5% of patients treated with telotristat ethyl experienced significant, dose-dependent weight gain, associated with reduced diarrhea severity and improved biochemical and metabolic parameters. Improved nutritional status could be an additional aspect of telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors. ClinicalTrials.gov identifier: NCT01677910.


Assuntos
Peso Corporal/efeitos dos fármacos , Diarreia/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenilalanina/uso terapêutico , Resultado do Tratamento , Triptofano Hidroxilase/antagonistas & inibidores
7.
Bone ; 113: 124-136, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29792935

RESUMO

LP533401 is an orally bioavailable small molecule that inhibits tryptophan hydroxylase-1, an enzyme responsible for the synthesis of gut-derived serotonin (GDS). Recently, we showed that increased GDS in rats with chronic kidney disease (CKD) affected bone strength and metabolism. We tested the hypothesis that treatment with LP533401 could reverse CKD-induced bone loss in uremia. Sixteen weeks after 5/6 nephrectomy, rats were randomized into untreated (CKD), treated with vehicle (VEH) and LP533401 at a dose of 30 or 100 mg/kg daily for 8 weeks. Treatment with LP533401 decreased serotonin turnover and restored bone mineral status, microarchitecture, and strength in CKD rats to the values observed in the controls. In parallel with the reduction of serotonin, serum phosphate levels also decreased, particularly in the LP533401, 100 mg/kg group. The mechanism underlying this phenomenon resulted from decreased expression of the renal VDR/FGF1R/Klotho/Npt2a/Npt2c axis, leading to elevated phosphate excretion in the kidneys. The elevated urinary phosphate excretion resulted in improved bone mineral status and strength in LP533401-treated rats. Unexpectedly, the standard VEH used in this model was able to reduce renal VDR/FGF1R/Klotho/Npt2a expression, leading to a compensatory increase in Npt2c mRNA levels, secondary disturbances in phosphate-regulated hormones and partial improvement in the mineral status of the trabecular bone. The decrease of serotonin synthesis together with the simultaneous reduction of renal Npt2a and Npt2c expression in rats treated with LP533401, 100 mg/kg led to an increase in 1,25(OH)2D3 levels; this mechanism seems to be particularly beneficial in relation to the mineral status of cortical bone.


Assuntos
Densidade Óssea/efeitos dos fármacos , Rim/efeitos dos fármacos , Pirimidinas/farmacologia , Serotonina/biossíntese , Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Rim/metabolismo , Masculino , Nefrectomia , Fosfatos/sangue , Ratos , Ratos Wistar , Insuficiência Renal Crônica , Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/metabolismo , Triptofano Hidroxilase/antagonistas & inibidores
8.
Trends Pharmacol Sci ; 39(6): 560-572, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29628275

RESUMO

The first step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase (TPH). There are two independent sources of the monoamine that have distinct functions: first, the TPH1-expressing enterochromaffin cells (ECs) of the gut; second, TPH2-expressing serotonergic neurons. TPH1-deficient mice revealed that peripheral 5-HT plays important roles in platelet function and in inflammatory and fibrotic diseases of gut, pancreas, lung, and liver. Therefore, TPH inhibitors were developed which cannot pass the blood-brain barrier to specifically block peripheral 5-HT synthesis. They showed therapeutic efficacy in several rodent disease models, and telotristat ethyl is the first TPH inhibitor to be approved for the treatment of carcinoid syndrome. We review this development and discuss further therapeutic options for these compounds.


Assuntos
Desenho de Drogas , Células Enterocromafins/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Serotonina/biossíntese , Triptofano Hidroxilase/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Células Enterocromafins/enzimologia , Humanos , Terapia de Alvo Molecular
9.
Future Oncol ; 14(12): 1155-1164, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29350062

RESUMO

Carcinoid syndrome (CS), characterized by diarrhea and flushing, is present in 20% of patients with neuroendocrine tumors at diagnosis and becomes more frequent with progression. The diarrhea of CS is caused mainly by tumoral secretion of serotonin. It may not be fully controlled by somatostatin analogs, the currently indicated drugs for symptomatic relief. Telotristat ethyl is a novel inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis. Administration of the drug decreases diarrhea in patients with CS. Telotristat ethyl was approved in February 2017 (USA) and September 2017 (European Commission) for the treatment of CS diarrhea in adults inadequately controlled by somatostatin analog alone. This drug is expected to greatly improve the health and quality of life of patients with CS diarrhea.


Assuntos
Diarreia/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Qualidade de Vida , Triptofano Hidroxilase/antagonistas & inibidores , Diarreia/etiologia , Humanos , Síndrome do Carcinoide Maligno/complicações , Síndrome do Carcinoide Maligno/epidemiologia , Síndrome do Carcinoide Maligno/patologia , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico , Prevalência , Pirimidinas/farmacologia , Somatostatina/biossíntese , Resultado do Tratamento , Triptofano Hidroxilase/metabolismo
10.
Chem Biol Drug Des ; 91(1): 202-212, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28719094

RESUMO

Serotonin (5-HT) is an important neurotransmitter and paracrine signaling molecule in the gastrointestinal tract. Two distinct tryptophan hydroxylases (TPH), TPH1 and TPH2, are the rate-limiting enzymes in the 5-HT biosynthesis process. TPH1 expression is mainly limited in the enterochromaffin cells and distributed in peripheries such as the skin and gut, while TPH2 is the predominant isoform in the CNS. In this study, mol002291 was screened as a drug-like compound from the TCM database for the inhibitor of TPH. After the enzymological analysis of mol002291, the analgesic effect of mol002291 was also further investigated in a PI-IBS visceral hyperalgesia rat model. Results from kinetic analysis showed that mol002291 specifically inhibited the TPH1 but did not act on TPH2, and the inhibitory action displayed characteristics of competitive inhibition. In addition, the results from abdominal withdrawal reflex (AWR) tests and electromyography (EMG) recordings showed that mol002291 significantly (p < .05) alleviated the visceral hyperalgesia. This result is entirely consistent with the fact that mol002291 significantly decreased the 5-HT content. These data demonstrated that mol002291 can attenuate visceral hyperalgesia mediated via reducing colonic 5-HT content. More important is that mol002291 could be developed as a novel prodrug and offer therapeutic avenues for the diseases where there is dysregulation of peripheral serotonergic pathways.


Assuntos
Analgésicos/química , Desenho de Drogas , Inibidores Enzimáticos/química , Pró-Fármacos/química , Triptofano Hidroxilase/antagonistas & inibidores , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Animais , Sítios de Ligação , Domínio Catalítico , Bases de Dados Factuais , Eletromiografia , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Cinética , Masculino , Simulação de Acoplamento Molecular , Pró-Fármacos/metabolismo , Pró-Fármacos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Triptofano Hidroxilase/metabolismo
11.
Am J Physiol Gastrointest Liver Physiol ; 313(5): G386-G398, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28774871

RESUMO

Necrotizing enterocolitis (NEC), a gastrointestinal inflammatory disease of unknown etiology that may also affect the liver, causes a great deal of morbidity and mortality in premature infants. We tested the hypothesis that signaling molecules, which are endogenous to the bowel, regulate the severity of intestinal and hepatic damage in an established murine NEC model. Specifically, we postulated that mucosal serotonin (5-HT), which is proinflammatory, would exacerbate experimental NEC and that oxytocin (OT), which is present in enteric neurons and is anti-inflammatory, would oppose it. Genetic deletion of the 5-HT transporter (SERT), which increases and prolongs effects of 5-HT, was found to increase the severity of systemic manifestations, intestinal inflammation, and associated hepatotoxicity of experimental NEC. In contrast, genetic deletion of tryptophan hydroxylase 1 (TPH1), which is responsible for 5-HT biosynthesis in enterochromaffin (EC) cells of the intestinal mucosa, and TPH inhibition with LP-920540 both decrease the severity of experimental NEC in the small intestine and liver. These observations suggest that 5-HT from EC cells helps to drive the inflammatory damage to the gut and liver that occurs in the murine NEC model. Administration of OT decreased, while the OT receptor antagonist atosiban exacerbated, the intestinal inflammation of experimental NEC. Data from the current investigation are consistent with the tested hypotheses-that the enteric signaling molecules, 5-HT (positively) and OT (negatively) regulate severity of inflammation in a mouse model of NEC. Moreover, we suggest that mucosally restricted inhibition of 5-HT biosynthesis and/or administration of OT may be useful in the treatment of NEC.NEW & NOTEWORTHY Serotonin (5-HT) and oxytocin reciprocally regulate the severity of intestinal inflammation and hepatotoxicity in a murine model of necrotizing enterocolitis (NEC). Selective depletion of mucosal 5-HT through genetic deletion or inhibition of tryptophan hydroxylase-1 ameliorates, while deletion of the 5-HT uptake transporter, which increases 5-HT availability, exacerbates the severity of NEC. In contrast, oxytocin reduces, while the oxytocin receptor antagonist atosiban enhances, NEC severity. Peripheral tryptophan hydroxylase inhibition may be useful in treatment of NEC.


Assuntos
Células Enterocromafins/metabolismo , Enterocolite Necrosante , Mucosa Intestinal , Fígado , Ocitocina/metabolismo , Fenilalanina/análogos & derivados , Pirimidinas/farmacologia , Serotonina , Transdução de Sinais , Triptofano Hidroxilase , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Enterocolite Necrosante/tratamento farmacológico , Enterocolite Necrosante/metabolismo , Enterocolite Necrosante/fisiopatologia , Inibidores Enzimáticos/farmacologia , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Fígado/metabolismo , Fígado/fisiopatologia , Camundongos , Fenilalanina/farmacologia , Serotonina/biossíntese , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Triptofano Hidroxilase/antagonistas & inibidores , Triptofano Hidroxilase/metabolismo
12.
Int J Mol Med ; 40(1): 155-163, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28560440

RESUMO

Inflammation and remodeling play a role in the pathogenesis of pulmonary arterial hypertension (PAH). Nuclear factor-κB (NF-κB) and nuclear factor of activated T cells-1 (NFAT-1) participate in inflammation and remodeling in a number of diseases. As a tryptophan hydroxylase inhibitor, 4-chloro-DL-phenylalanine (PCPA) had been reported to exert anti-inflammatory and remodeling effects. Therefore, we hypothesized that PCPA may attenuate monocrotaline (MCT)-induced PAH through the NFAT-1 and NF-κB signaling pathways. In order to confirm our hypothesis, we divided 68 Sprague-Dawley male rats into 4 groups as follows: the control, MCT, MCT + P1 and MCT + P2 groups. MCT was administered at a dose of 60 mg/kg once via intraperitoneal injection. PCPA was administered via intraperitoneal injection at a dose of 50 or 100 mg/kg once daily for 21 consecutive days. We then measured the hemodynamic index and morphological analysis was carried out on the lung tissues. Western blot analysis and immunohistochemistry were used to examine the levels of NFAT-1 and NF-κB p-65. The expression levels of phosphorylated inhibitor of NF-κB kinase (p-IKK), IKK, phosphorylated extracellular signal­regulated kinase (p-ERK), ERK, intercellular adhesion molecule-1 (ICAM-1) and inter-leukin-6 (IL-6) were examined by western blot analysis. MCT was found to significantly induce PAH, with inflammation and remodeling of the lung tissues. This was associatd with an increased expression of NFAT-1, p-IKK, p-ERK and nuclear p65. PCPA significantly attenuated MCT-induced inflammation and arterial remodeling, and decreased the expression of NFAT-1, as well as that of relevant proteins of the NF-κB signaling pathway. The above-mentioned findings suggest that the inhibitory effects of PCPA on MCT-induced inflammation and arterial remodeling are related to the downregulation of the NFAT-1 and NF-κB signaling pathways in rats with PAH.


Assuntos
Fenclonina/análogos & derivados , Hipertensão Pulmonar , Monocrotalina/toxicidade , Fatores de Transcrição NFATC/metabolismo , Fator de Transcrição RelA/metabolismo , Triptofano Hidroxilase/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Fenclonina/farmacologia , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Triptofano Hidroxilase/metabolismo
14.
Drugs ; 77(7): 793-798, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28382568

RESUMO

Telotristat ethyl (Xermelo™) is a peripheral tryptophan hydroxylase (TPH) inhibitor that was developed by Lexicon Pharmaceuticals, Inc. for the treatment of carcinoid syndrome. Many neuroendocrine tumours secrete serotonin (5-HT) into the blood stream, resulting in a number of symptoms, notably diarrhoea. Telotristat ethyl inhibits TPH, thereby reducing the production of 5-HT. In February 2017, telotristat ethyl was approved in the USA for the treatment of carcinoid syndrome diarrhoea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. This article summarizes the milestones in the development of telotristat ethyl leading to this first global approval.


Assuntos
Diarreia/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/administração & dosagem , Triptofano Hidroxilase/antagonistas & inibidores , Animais , Aprovação de Drogas , Quimioterapia Combinada , Humanos , Tumores Neuroendócrinos/complicações , Fenilalanina/administração & dosagem , Fenilalanina/efeitos adversos , Fenilalanina/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Somatostatina/análogos & derivados , Estados Unidos , United States Food and Drug Administration
15.
Bioorg Med Chem Lett ; 27(3): 413-419, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28041831

RESUMO

As a follow-up to the discovery of our spirocyclic proline-based TPH1 inhibitor lead, we describe the optimization of this scaffold. Through a combination of X-ray co-crystal structure guided design and an in vivo screen, new substitutions in the lipophilic region of the inhibitors were identified. This effort led to new TPH1 inhibitors with in vivo efficacy when dosed as their corresponding ethyl ester prodrugs. In particular, 15b (KAR5585), the prodrug of the potent TPH1 inhibitor 15a (KAR5417), showed robust reduction of intestinal serotonin (5-HT) levels in mice. Furthermore, oral administration of 15b generated high and sustained systemic exposure of the active parent 15a in rats and dogs. KAR5585 was selected for further pharmacological evaluation in disease models associated with a dysfunctional peripheral 5-HT system.


Assuntos
Pró-Fármacos/química , Prolina/análogos & derivados , Pirimidinas/química , Compostos de Espiro/química , Triptofano Hidroxilase/antagonistas & inibidores , Triptofano Hidroxilase/metabolismo , Animais , Sítios de Ligação , Cães , Meia-Vida , Humanos , Concentração Inibidora 50 , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Prolina/metabolismo , Prolina/farmacologia , Estrutura Terciária de Proteína , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Ratos , Serotonina/metabolismo , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
16.
Expert Opin Ther Targets ; 21(2): 167-180, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27973928

RESUMO

INTRODUCTION: The ancient and ubiquitous monoamine signalling molecules serotonin, dopamine, norepinephrine, and epinephrine are involved in multiple physiological functions. The aromatic amino acid hydroxylases tyrosine hydroxylase (TH), tryptophan hydroxylase 1 (TPH1), and tryptophan hydroxylase 2 (TPH2) catalyse the rate-limiting steps in the biosynthesis of these monoamines. Genetic variants of TH, TPH1, and TPH2 genes are associated with neuropsychiatric disorders. The interest in these enzymes as therapeutic targets is increasing as new roles of these monoamines have been discovered, not only in brain function and disease, but also in development, cardiovascular function, energy and bone homeostasis, gastrointestinal motility, hemostasis, and liver function. Areas covered: Physiological roles of TH, TPH1, and TPH2. Enzyme structures, catalytic and regulatory mechanisms, animal models, and associated diseases. Interactions with inhibitors, pharmacological chaperones, and regulatory proteins relevant for drug development. Expert opinion: Established inhibitors of these enzymes mainly target their amino acid substrate binding site, while tetrahydrobiopterin analogues, iron chelators, and allosteric ligands are less studied. New insights into monoamine biology and 3D-structural information and new computational/experimental tools have triggered the development of a new generation of more selective inhibitors and pharmacological chaperones. The enzyme complexes with their regulatory 14-3-3 proteins are also emerging as therapeutic targets.


Assuntos
Desenho de Drogas , Triptofano Hidroxilase/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Proteínas 14-3-3/metabolismo , Animais , Sítios de Ligação , Inibidores Enzimáticos/farmacologia , Variação Genética , Humanos , Ligantes , Chaperonas Moleculares/farmacologia , Terapia de Alvo Molecular , Triptofano Hidroxilase/genética , Tirosina 3-Mono-Oxigenase/genética
17.
J Pharmacol Exp Ther ; 360(2): 267-279, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27927914

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive disease defined by a chronic elevation in pulmonary arterial pressure with extensive pulmonary vascular remodeling and perivascular inflammation characterized by an accumulation of macrophages, lymphocytes, dendritic cells, and mast cells. Although the exact etiology of the disease is unknown, clinical as well as preclinical data strongly implicate a role for serotonin (5-HT) in the process. Here, we investigated the chronic effects of pharmacological inhibition of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in peripheral 5-HT biosynthesis, in two preclinical models of pulmonary hypertension (PH), the monocrotaline (MCT) rat and the semaxanib (SUGEN, Medinoah, Suzhou, China)-hypoxia rat. In both PH models, ethyl (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate and ethyl (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1 H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, novel orally active TPH1 inhibitors with nanomolar in vitro potency, decreased serum, gut, and lung 5-HT levels in a dose-dependent manner and significantly reduced pulmonary arterial pressure, and pulmonary vessel wall thickness and occlusion in male rats. In the MCT rat model, decreases in lung 5-HT significantly correlated with reductions in histamine levels and mast cell number (P < 0.001, r2 = 0.88). In contrast, neither ambrisentan nor tadalafil, which are vasodilators approved for the treatment of PAH, reduced mast cell number or 5-HT levels, nor were they as effective in treating the vascular remodeling as were the TPH1 inhibitors. When administered in combination with ambrisentan, the TPH1 inhibitors showed an additive effect on pulmonary vascular remodeling and pressures. These data demonstrate that in addition to reducing vascular remodeling, TPH1 inhibition has the added benefit of reducing the perivascular mast cell accumulation associated with PH.


Assuntos
Inibidores Enzimáticos/farmacologia , Hipertensão Pulmonar/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Triptofano Hidroxilase/antagonistas & inibidores , Remodelação Vascular/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Serotonina/sangue , Serotonina/metabolismo , Triptofano Hidroxilase/metabolismo
18.
J Clin Oncol ; 35(1): 14-23, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27918724

RESUMO

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.


Assuntos
Defecação/efeitos dos fármacos , Diarreia/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Idoso , Antineoplásicos Hormonais/uso terapêutico , Diarreia/etiologia , Diarreia/urina , Método Duplo-Cego , Feminino , Humanos , Ácido Hidroxi-Indolacético/urina , Masculino , Síndrome do Carcinoide Maligno/complicações , Síndrome do Carcinoide Maligno/urina , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Fenilalanina/efeitos adversos , Fenilalanina/uso terapêutico , Pirimidinas/efeitos adversos , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Triptofano Hidroxilase/antagonistas & inibidores , gama-Glutamiltransferase/sangue
19.
Expert Opin Pharmacother ; 17(18): 2487-2498, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27817224

RESUMO

INTRODUCTION: Many patients with neuroendocrine tumour-related carcinoid syndrome treated with somatostatin analogues (SSA) won't achieve adequate symptom relief with the SSA alone; new treatment options are required. Telotristat ethyl is a tryptophan hydroxylase inhibitor, developed for the treatment of carcinoid syndrome. Areas covered: This review summarises the evidence supporting the role of telotristat ethyl in the management of carcinoid syndrome. Rationale, pharmacodynamics, pharmacokinetics, metabolism, clinical experience, efficacy and toxicity profiles are covered. Expert opinion: The efficacy of telotristat ethyl in producing a statistically-significant and clinically-meaningful reduction in daily bowel movements has been confirmed in phase III clinical trials. Two pivotal trials, TELESTAR and TELECAST, explored the role of telotristat ethyl in the management of patients with carcinoid syndrome refractory to SSAs focusing on patients with ≥4 and <4 daily bowel movements, respectively. In addition, benefit was confirmed in patient-reported outcomes. Based on activity and safe toxicity profile, telotristat ethyl is pending regulatory agencies evaluation and is likely to add to the armamentarium used to treat carcinoid syndrome. Long-term safety and efficacy data will be available from the ongoing TELEPATH study. The impact on carcinoid heart disease, mesenteric fibrosis and other long-term complications of carcinoid syndrome as well as its role earlier in patients' pathways remain investigational.


Assuntos
Síndrome do Carcinoide Maligno/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Triptofano Hidroxilase/antagonistas & inibidores , Animais , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/tratamento farmacológico , Tumor Carcinoide/metabolismo , Ensaios Clínicos como Assunto/métodos , Humanos , Síndrome do Carcinoide Maligno/diagnóstico , Síndrome do Carcinoide Maligno/metabolismo , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico , Pirimidinas/farmacologia , Somatostatina/análogos & derivados , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Triptofano Hidroxilase/metabolismo
20.
Sci Rep ; 6: 30059, 2016 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-27444653

RESUMO

The biogenic amine serotonin (5-HT) is a multi-faceted hormone that is synthesized from dietary tryptophan with the rate limiting step being catalyzed by the enzyme tryptophan hydroxylase (TPH). The therapeutic potential of peripheral 5-HT synthesis inhibitors has been demonstrated in a number of clinical and pre-clinical studies in diseases including carcinoid syndrome, lung fibrosis, ulcerative colitis and obesity. Due to the long half-life of 5-HT in blood and lung, changes in steady-state levels are slow to manifest themselves. Here, the administration of stable isotope labeled tryptophan (heavy "h-Trp") and resultant in vivo conversion to h-5-HT is used to monitor 5-HT synthesis in rats. Dose responses for the blockade of h-5-HT appearance in blood with the TPH inhibitors L-para-chlorophenylalanine (30 and 100 mg/kg) and telotristat etiprate (6, 20 and 60 mg/kg), demonstrated that the method enables robust quantification of pharmacodynamic effects on a short time-scale, opening the possibility for rapid screening of TPH1 inhibitors in vivo. In the bleomycin-induced lung fibrosis rat model, the mechanism of lung 5-HT increase was investigated using a combination of synthesis and steady state 5-HT measurement. Elevated 5-HT synthesis measured in the injured lungs was an early predictor of disease induced increases in total 5-HT.


Assuntos
Agonistas do Receptor de Serotonina/farmacocinética , Serotonina/biossíntese , Animais , Modelos Animais de Doenças , Fibrose/patologia , Marcação por Isótopo , Doenças Pulmonares Intersticiais/patologia , Ratos , Triptofano/administração & dosagem , Triptofano Hidroxilase/antagonistas & inibidores
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