Takahiro Hata

JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, suppresses food intake and gastric emptying with the elevation of plasma peptide YY and glucagon-like peptide-1 in a dietary fat-dependent manner

The microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. In this study, we investigated the effects of diethyl-2-({3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl) amino] phenyl}acetyloxymethyl)-2-phenylmalonate (JTT-130), a novel intestine-specific MTP inhibitor, on food intake, gastric emptying, and gut peptides using Sprague-Dawley rats fed 3.1% fat, 13% fat, or 35% fat diets. JTT-130 treatment suppressed cumulative food intake and gastric emptying in rats fed a 35% fat diet, but not a 3.1% fat diet. In rats fed a 13% fat diet, JTT-130 treatment decreased cumulative food intake but not gastric emptying. In addition, treatment with orlistat, a lipase inhibitor, completely abolished the reduction of food intake and gastric emptying by JTT-130 in rats fed a 35% fat diet. On the other hand, JTT-130 treatment increased the plasma concentrations of gut peptides, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) but not cholecystokinin, in the portal vein in rats fed a 35% fat diet. These elevations in PYY and GLP-1 were also abolished by treatment with orlistat. Furthermore, JTT-130 treatment in rats fed a 35% fat diet increased the contents of triglycerides and free fatty acids in the intestinal lumen, which might contribute to the elevation of PYY and GLP-1 levels. The present findings indicate that JTT-130 causes satiety responses, decreased food intake, and gastric emptying in a dietary fat-dependent manner, with enhanced production of gut peptides such as PYY and GLP-1 from the intestine.

Pharmacological characterization of diethyl-2-({3-dimethylcarbamoyl-4-[(4'-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetyloxymethyl)-2-phenylmalonate (JTT-130), an intestine-specific inhibitor of microsomal triglyceride transfer protein.

Inhibitors of microsomal triglyceride transfer protein (MTP) expressed in the liver and small intestine are potential candidates for lipid-lowering agents. However, inhibition of hepatic MTP could lead to significant safety issues such as fatty liver disease. To develop a specific inhibitor of intestinal MTP, JTT-130 [diethyl-2-({3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetyloxymethyl)-2-phenylmalonate], was designed to be rapidly hydrolyzed in the absorption process. Here, we describe JTT-130, an intestine-specific MTP inhibitor, and evaluate its pharmacological properties. In in vitro metabolic stability tests, JTT-130 was readily hydrolyzed during incubation with liver S9 from humans, hamsters, and rats. In an in vitro triglyceride (TG) transfer assay with human intestinal MTP, JTT-130 potently inhibited TG transfer activity with an IC50 value of 0.83 nM. When orally administered to hamsters, JTT-130 significantly suppressed an increase in chylomicron-TG after olive oil loading at 0.3 mg/kg and above but did not inhibit TG secretion from the liver at doses of up to 1000 mg/kg, indicating an inhibitory action highly specific for the small intestine. In rats orally administered [14C]triolein, JTT-130 potently suppressed an increase in blood 14C radioactivity and increased 14C radioactivity in the upper small intestine and the intestinal lumen. In hyperlipidemic hamsters fed a high-fat and high-cholesterol diet, repeated dosing with JTT-130 for 2 weeks reduced TG and cholesterol levels in the plasma and TG content in the liver. These results indicated that JTT-130 is a potent inhibitor specific to intestinal MTP and suggested that JTT-130 would be a useful compound for the treatment of dyslipidemia without inducing hepatotoxicity.

SAR Exploration Guided by LE and Fsp3: Discovery of a Selective and Orally Efficacious RORγ Inhibitor

A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor 3z.

JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, ameliorates impaired glucose and lipid metabolism in Zucker diabetic fatty rats.

Aim: Microsomal triglyceride transfer protein (MTP) takes part in the mobilization of triglyceride‐rich lipoproteins from enterocytes and hepatocytes. We investigated the effects of JTT‐130, a novel intestine‐specific MTP inhibitor, on impaired glucose and lipid metabolism in Zucker diabetic fatty (ZDF) rats.

A high-fat diet inhibits the progression of diabetes mellitus in type 2 diabetic rats

It is well known that rats and mice, when fed a high-fat diet, develop obesity associated with abnormal glycolipid metabolism. In this study, we investigated the effects of a high-fat diet on a diabetic rat model, Spontaneously Diabetic Torii (SDT), which develops diabetes due to decreased insulin production and secretion with age. We hypothesized that a high-fat diet would accelerate the induction of diabetes in this model. The SDT rats were divided into 2 groups, which were fed a high-fat diet or standard diet for 16 weeks. The group fed a high-fat diet developed obesity, hyperinsulinemia, and hyperlipidemia until 16 weeks of age. Before 16 weeks of age, hyperglycemia accompanied by hypoinsulinemia developed in the group on a standard diet, but serum glucose levels were comparable in both groups. After 16 weeks of age, the group on a standard diet showed an increase in serum glucose levels and a decrease in serum insulin levels. Unexpectedly, in the group on the high-fat diet, we observed a suppressed of the progression of hyperglycemia/hypoinsulinemia. Histopathological observation revealed more pancreatic beta cells in the group on the high-fat diet. This study suggests that feeding SDT rats a high-fat diet induces obesity, hyperinsulinemia, and hyperlipidemia, but not hyperglycemia, until 16 weeks of age. Thereafter, age-dependent progress of hyperglycemia and hypoinsulinemia was delayed by a high-fat diet. The hyperfunction of pancreatic beta cells induced by a high-fat diet before the onset of hyperglycemia appears to suppress development of hyperglycemia/hypoinsulinemia.

JTT‐130, a novel intestine‐specific inhibitor of microsomal triglyceride transfer protein, suppresses high fat diet‐induced obesity and glucose intolerance in Sprague‐Dawley rats

Aim: Microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride‐rich lipoproteins from enterocytes and hepatocytes. We investigated the effects of JTT‐130, a novel intestine‐specific MTP inhibitor, on high fat diet‐induced obesity and glucose intolerance.

JTT-130, a Novel Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein, Reduces Food Preference for Fat

Microsomal triglyceride transfer protein (MTP) is involved in the assembly and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. JTT-130 is a novel intestine-specific MTP inhibitor, which has been shown to be useful in the prevention and treatment of dyslipidemia, obesity, and diabetes. JTT-130 has also been shown to suppress food intake in a dietary fat-dependent manner in rats. However, whether JTT-130 enables changes in food preference and nutrient consumption remains to be determined. Therefore, the aim of the present study was to investigate the effects of JTT-130 on food preference in rat under free access to two different diets containing 3.3% fat (low-fat diet, LF diet) and 35% fat (high-fat diet, HF diet). JTT-130 decreased HF diet intake and increased LF diet intake, resulting in a change in ratio of caloric intake from LF and HF diets to total caloric intake. In addition, macronutrient analysis revealed that JTT-130 did not affect carbohydrate consumption but significantly decreased fat consumption (P < 0.01). These findings suggest that JTT-130 not only inhibits fat absorption, but also suppresses food intake and specifically reduces food preference for fat. Therefore, JTT-130 is expected to provide a new option for the prevention and treatment of obesity and obesity-related metabolic disorders.

JTE-852, a novel spleen tyrosine kinase inhibitor, blocks mediator secretion from mast cells with immunoglobulin E crosslinking

ABSTRACT Mast cells stimulated by immunoglobulin E (IgE)‐crosslinking secrete mediators, which are mainly categorized into three groups: granule contents, arachidonate metabolites, and cytokines. These mediators play important roles in pathogenesis of allergic diseases; indeed, some conventional drugs which target the mediators are used in clinical practices. However, these drugs are not yet sufficient enough in their efficacy. That is because most of them are blockers of single mediators and are unable to prevent simultaneously various reactions caused by the three group mediators. Spleen tyrosine kinase (Syk) is a non‐receptor protein tyrosine kinase. In mast cells, Syk locates at almost top of the signal cascades induced by IgE‐crosslinking and plays pivotal roles in secretion of the three groups of mediators. Therefore, inhibition of Syk would suppress the secretion of all the mediators from mast cells and be a promising‐treatment strategy for allergic diseases. In the present study, we characterized pharmacological profiles of JTE‐852, which was identified as a novel Syk inhibitor. JTE‐852 inhibited kinase activity of Syk in an adenosine 5′‐triphosphate (ATP)‐competitive fashion. JTE‐852 also blocked the secretion of granule contents, arachidonate metabolites, and cytokines from mast cells stimulated by IgE‐crosslinking, with similar potencies. The results suggest that JTE‐852 is supposed to prevent various allergic reactions caused by the three group mediators in vivo. In fact, oral gavage of JTE‐852 attenuated an allergic reaction mediated by histamine, which is a representative of the three groups of mediators. JTE‐852 is expected to be a novel, highly‐efficacious, and orally available anti‐allergic drug.

JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits improved transrepression/transactivation dissociation

Abstract Classic glucocorticoids that have outstanding anti‐inflammatory effects are still widely prescribed for the treatment of various inflammatory and autoimmune diseases. Conversely, glucocorticoids cause numerous unwanted side effects, particularly systemically dosed glucocorticoids. Therefore, selective glucocorticoid receptor modulator (SGRM), which maintains beneficial anti‐inflammatory effects while reducing the occurrence of side effects, is one of the most anticipated drugs. However, there have been no SGRMs marketed to date. The assumption is that there are two major mechanisms of action of glucocorticoids via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, the anti‐inflammatory effects of glucocorticoids are mostly mediated through TR, while the side effects associated with glucocorticoids are largely caused by TA. We started to evaluate novel orally available SGRMs that maintain anti‐inflammatory effects while minimizing adverse effects by favoring TR over TA. Based on this evaluation, we discovered JTP‐117968, (4b’S,7′R,8a’S)‐4b’‐benzyl‐7′‐hydroxy‐N‐(2‐methylpyridin‐3‐yl)‐7′‐(trifluoromethyl)‐4b’,6′,7′,8′,8a’,10’‐hexahydro‐5′H‐spiro[cyclopropane‐1,9′‐phenanthrene]‐2′‐carboxamide, a non‐steroidal SGRM. JTP‐117968 has partial TR activity, but exhibits extremely low TA activity. The maximum TR efficacy of JTP‐117968 was comparable to its structural analogue, PF‐802, (4bS,7 R,8aR)‐4b‐Benzyl‐7‐hydroxy‐N‐(2‐methylpyridin‐3‐yl)‐7‐(trifluoromethyl)‐4b,5,6,7,8,8a,9,10‐octahydrophenanthrene‐2‐carboxamide, which is the active form of Fosdagrocorat that has been developed clinically as a first‐in‐class orally available SGRM. Remarkably, the TA activity of JTP‐117968 was much weaker than PF‐802 not only in in vitro assays, but also in in vivo mice experiments. These findings indicate that JTP‐117968 exhibits improved TR/TA dissociation because the compound has significantly lower TA activity compared with an already reported SGRM. Therefore, JTP‐117968 is expected to be a useful compound for evaluating ideal SGRMs in the future.

JTE-852, a novel spleen tyrosine kinase inhibitor, blocks antigen-induced allergic reactions in rats

Conventional clinical treatments for allergy management remain suboptimal; new, orally available medications that improve a wide range of allergic signs have been desired. We previously demonstrated that JTE-852, a novel spleen tyrosine kinase inhibitor, potently and simultaneously suppresses secretion of granule contents, arachidonate metabolites, and cytokines from mast cells stimulated by immunoglobulin E-crosslinking. In the present study, we investigated the effects of JTE-852 in four rat models (sneezing, rhinorrhea, airway constriction, and airway inflammation) as representatives of allergy models. Rats were sensitized and challenged with antigen. Allergic reactions developed after challenge were detected. JTE-852 and current anti-allergic drugs (ketotifen, pranlukast, and prednisolone) were administered orally before challenge. JTE-852 showed significant blocking effects on antigen-induced allergic reactions in all models, indicating that JTE-852 in oral dosage form would improve a wide range of allergic signs. The current anti-allergic drugs, on the other hand, failed to display significant suppression in several models. Because JTE-852 suppresses the secretion of all three groups of allergic mediators from mast cells, it would be capable of targeting signs that current drugs cannot sufficiently relieve. We anticipate JTE-852 to be a promising new anti-allergic drug that is potentially more effective than conventional drugs.