Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

The sphingosine-1-phosphate receptor modulator, FTY720, prevents the incidence of diabetes in Spontaneously Diabetic Torii rats.

The sphingosine-1-phosphate (S1P) receptor modulator regulates lymphocyte trafficking, resulting in its depletion from circulation, which ultimately causes immunosuppression. In this study, we investigated the preventive effect of fingolimod (FTY720) in the non-obese type 2 diabetic model, Spontaneously Diabetic Torii (SDT) rats. The S1P receptor modulator, FTY720 (0.3 mg/kg p.o.), was administered for 12 weeks to SDT rats from 5 to 17 weeks of age. Based on our findings, FTY720 could suppress the incidence of diabetes in SDT rats. Further, glucose intolerance was improved in FTY720-treated SDT rats at 14 weeks of age. Based on the haematological and histological analyses performed at 17 to 18 weeks of age, a decrease in lymphocytes and monocytes in the peripheral blood and a decrease in lymphocyte and atrophy in spleen occurred in the FTY720-treated SDT rats. Furthermore, the pancreatic changes, such as inflammation, atrophy, and fibrosis in islets observed in SDT rats were improved by FTY720 treatment. These findings suggest that the immunomodulatory effects of FTY720 reduced the pancreatic lesion in SDT rats, thereby demonstrating its preventive effect against diabetes. The development of diabetes in SDT rats is related to disorders of the immune system. However, the S1P receptor modulator may be useful for treating type 2 diabetes.

A Novel TNF-α Converting Enzyme (TACE) Selective Inhibitor JTP-96193 Prevents Insulin Resistance in KK-Ay Type 2 Diabetic Mice and Diabetic Peripheral Neuropathy in Type 1 Diabetic Mice.

Tumor necrosis factor-α (TNF-α) converting enzyme/a disintegrin and metalloproteinase domain-containing protein 17 (TACE/ADAM17) is a key sheddase that releases TNF-α from its inactive precursor and is thought as a new drug target to inhibit TNF-α production. In the present study, pharmacological effects of a novel TACE selective inhibitor, JTP-96193, on type 2 diabetes and diabetic peripheral neuropathy (DPN) as its major complication was examined. Enzyme inhibitory activity of JTP-96193 on TACE and other ADAMs was measured in in vitro. High fat-induced obese mice and type 2 diabetic KK-Ay mice were used to evaluate the effect of JTP-96193 on insulin resistance. Finally, streptozotocin (STZ)-induced diabetic mice were treated with JTP-96193 to evaluate the sciatic motor nerve conduction velocities (MNCV). JTP-96193 selectively inhibited human TACE activity with IC50 value of 5.4 nM and showed more than 1800-fold selectivity against other matrix metalloproteinases. In mouse models of obesity and diabetes, JTP-96193 reduced the TNF-α release from the fat tissue and prevented development of diabetes and improved insulin resistance, respectively. Furthermore, JTP-96193 prevented delay of sciatic MNCV without any effects on blood glucose or insulin levels in STZ-induced diabetic mice. TACE inhibitor is effective on insulin resistance and DPN independent from glucose-lowering effect. These pharmacological properties of JTP-96193 may be helpful to treat type 2 diabetes accompanied by its microvascular complications.

Bodily distress syndrome after receiving vaccines: A case report.

A 48-year-old woman presented with various symptoms, including widespread body pains, insomnia, palpitations, and shortness of breath, after receiving tetanus toxoid. After going through multiple visits to clinicians of various subspecialties, she was referred to our infectious diseases clinic. She was diagnosed with bodily distress syndrome (BDS), possibly triggered by tetanus toxoid injection. Her symptoms improved shortly after reassurance and medical management. Functional disorders such as BDS can occur after vaccinations, and one must be aware of this possibility in patients with multiple symptoms after receiving vaccines.

Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold.

Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.

Ternary crystal structure of human RORγ ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction.

Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4+ T cells (Th17 cells). Structure-based drug design has proven fruitful in the development of inhibitors targeting the ligand binding domain (LBD) of RORγ. Here, we present the crystal structure of a novel RORγ inhibitor co-complex, in the presence of a corepressor (CoR) peptide. This ternary complex with compound T reveals the structural basis for an inhibitory mechanism different from the previously reported inverse agonist. Compared to the inverse agonist, compound T induces about 2 Šshift of helix 5 (H5) backbone and side-chain conformational changes of Met365 on H5. These conformational changes correlate to reduced CoR peptide binding to RORγ-LBD in the presence of compound T, which suggests that the shift of H5 is responsible. This crystal structure analysis will provide useful information for the development of novel and efficacious drugs for autoimmune disorders.

A novel JAK inhibitor JTE-052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents.

Janus kinases (JAKs) are required for several inflammatory cytokine signalling pathways and are implicated in the pathogenesis of chronic dermatitis, including atopic dermatitis and psoriasis. JAK inhibitors are therefore promising therapeutic candidates for chronic dermatitis. In this study, we evaluated the effects of the novel JAK inhibitor JTE-052 on inflammatory responses associated with chronic dermatitis, and compared its profile with those of conventional therapeutic agents in rodent models of chronic dermatitis. JTE-052 inhibited the Th1-, Th2- and Th17-type inflammatory responses of human T cells and mast cells in vitro. Oral administration of JTE-052 inhibited skin inflammation in hapten-induced chronic dermatitis in mice, associated with reduced levels of inflammatory cytokines in the skin and immunoglobulin (Ig) E in serum. In contrast, although ciclosporin partly inhibited skin inflammation, it did not reduce interleukin (IL)-4 production in skin, and enhanced IgE production in serum. Oral administration of JTE-052 also inhibited skin inflammation in mouse models of atopic dermatitis and psoriasis induced by a mite extract, thymic stromal lymphopoietin or IL-23. The maximal efficacy of JTE-052 in these dermatitis models was superior to the conventional therapeutic agents, ciclosporin and methotrexate. Topical application of JTE-052 ointment ameliorated hapten-induced chronic dermatitis in rats more effectively than tacrolimus ointment. Furthermore, JTE-052 ointment did not cause the thinning of normal skin associated with topical corticosteroids. These results indicate that JTE-052 is a promising candidate as an anti-inflammatory drug for various types of chronic dermatitis, with a distinctly different profile from conventional therapy following either oral or topical application.

Ternary complex of human RORγ ligand-binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment.

Retinoid-related orphan receptor gamma (RORγ) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORγ, we have determined the first crystal structure of a ternary complex containing RORγ ligand-binding domain (LBD) bound with a novel synthetic inhibitor and a repressor peptide, 22-mer peptide from silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Comparison of a binary complex of nonliganded (apo) RORγ-LBD with a nuclear receptor co-activator (NCoA-1) peptide has shown that our inhibitor displays a unique mechanism different from those caused by natural inhibitor, ursolic acid (UA). The compound unprecedentedly induces indirect disruption of a hydrogen bond between His479 on helix 11 (H11) and Tyr502 on H12, which is crucial for active conformation. This crystallographic study will allow us to develop novel synthetic compounds for autoimmune disease therapy.

SAR Exploration Guided by LE and Fsp(3): 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.

Somatic symptoms after sexual behavior with fear of four sexually transmitted diseases: A proposal of novel disorder.

Somatic symptom disorder (SSD) often leads to frequent doctor visit not only to psychiatrists but also to various kinds of physicians. We encountered four cases of SSD, particularly associated with sexual intercourse and fear of sexually transmitted diseases (STDs). To best of our knowledge, there is no independent clinical entity assigned to this phenomenon. Here, we propose a variation of SSD called four STD as an independent clinical entity since the presentation of this disorder is very distinctive, and lack of awareness of it may lead to unnecessary laboratory workup and antimicrobial prescription as well as augmented anxiety of the patients with potential "doctor shopping." Further studies are needed to elucidate the pathophysiology, diagnosis, and treatment of this disorder.

Female spontaneously diabetic Torii fatty rats develop nonalcoholic steatohepatitis-like hepatic lesions.

AIM: To investigate the histological features of the liver in spontaneously diabetic Torii (SDT) fatty rats compared with age-matched Sprague-Dawley (SD) rats. METHODS: Female SDT Lepr(fa) (SDT fatty) rats and age-matched SD rats were fed ad libitum. Body weight and biochemical parameters, such as serum glucose, triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels as well as fatty acid and TG accumulation in the liver were evaluated at 8 wk of age in the non-fasting state and at 8-wk intervals from 8 to 40 wk of age. Histopathological examinations of the liver were performed using hematoxylin and eosin and Sirius Red staining as well as double staining for ED-1 and toluidine blue. The expression of genes involved in TG synthesis, inflammation, and fibrosis was examined in the liver. RESULTS: SDT fatty rats showed significantly increased body weight compared with SD rats. Serum glucose, TG, and TC levels were significantly higher in SDT fatty rats compared with SD rats. The serum AST and ALT levels in SDT fatty rats were significantly elevated at 8 wk of age compared with the levels in SD rats. Hepatic TG content was marked in SDT fatty rats from 8 to 32 wk of age. Histopathologically, severe hepatosteatosis accompanied by inflammation was observed at 8 wk of age, and fibrosis started to occur at 32 wk of age. Furthermore, Sirius Red and ED-1 staining were increased in the liver at 32 wk of age. Hepatic gene expression related to TG synthesis, inflammation and fibrosis tended to increase in SDT fatty rats compared with SD rats, and the gene expression related to TG secretion was decreased in SDT fatty rats compared with SD rats. CONCLUSION: Female SDT fatty rats have the potential to become an important animal model of nonalcoholic steatohepatitis with type 2 diabetes and obesity.

Rumor-Related and Exclusive Behavior Coverage in Internet News Reports Following the 2009 H1N1 Influenza Outbreak in Japan.

OBJECTIVE: We sought to elucidate news article reporting of adverse public psychosocial behaviors, in particular, rumor-related coverage (eg, panic, demagoguery) and exclusive behavior coverage (negative behaviors, eg, discrimination, bullying) during the 2009 influenza A (H1N1) influenza pandemic in Japan. METHODS: We examined 154 Internet news-site articles reporting adverse public psychosocial responses in the first 60 days of the outbreak. Rumor-related coverage and exclusive behavior coverage were dichotomously coded as included or not. Moreover, we assessed whether or not health information (eg, coping methods, virus toxicity information) or emphasis on information quality (eg, importance of information, cautions about overreactions) were simultaneously reported. RESULTS: Rumor-related coverage (n=120, 77.9%) was less likely to simultaneously report public health information (eg, toxicity information, health support information, and cautions about overreactions; P<.05). Conversely, exclusive behavior coverage (n=41, 26.6%) was more likely to report public health information (P<.05). CONCLUSIONS: Rumor-related coverage was less likely to have accompanying public health information, whereas exclusive behavior coverage was more likely to include it. During public health crises, it is essential to understand that rumors and exclusive behaviors have adverse effects on the public and that accompanying public health information may help people take proactive coping actions.

Contribution of hyperglycemia on diabetic complications in obese type 2 diabetic SDT fatty rats: effects of SGLT inhibitor phlorizin.

The spontaneously diabetic torii (SDT) fatty rat is a new model of type 2 diabetes showing overt obesity, hyperglycemia and hyperlipidemia. With early onset of diabetes mellitus, diabetic microvascular complications, including nephropathy, peripheral neuropathy and retinopathy, are observed at young ages. In the present study, blood glucose levels of female SDT fatty rats were controlled with phlorizin, a non-selective SGLT inhibitor, to examine whether and how these complications are caused by hyperglycemia. Phlorizin treatment adequately controlled plasma glucose levels during the experiment. At 29 weeks of age, urinary albumin excretion considerably increased in SDT fatty rats. Glomerulosclerosis and tubular pathological findings also indicate diabetic nephropathy. These renal parameters tended to decrease with phlorizin; however, effects were partial. Sciatic nerve conduction velocities were significantly delayed in SDT fatty rats compared with Sprague-Dawley (SD) rats. Intraepidermal nerve fiber density, an indicator of subclinical small nerve fiber neuropathy, significantly decreased in SDT fatty rats. Retinal dysfunction (prolongation of peak latency for oscillatory potential in electroretinograms) and histopathological eye abnormalities, including retinal folding and mature cataracts were also observed. Both nerve and eye disorders were prevented with phlorizin. These findings indicate that severe hyperglycemia mainly causes diabetic complications in SDT fatty rats. However, other factors, such as hyperlipidemia and hypertension, may affect diabetic nephropathy. These characteristics of diabetic complications will become helpful in evaluating new drugs for diabetic complications using SDT fatty rats.

Effects of unilateral nephrectomy on renal function in male Spontaneously Diabetic Torii fatty rats: a novel obese type 2 diabetic model.

The Spontaneously Diabetic Torii (SDT) fatty rat is a new model for obese type 2 diabetes. The aim of the present study was to investigate the effect of 1/2 nephrectomy (Nx) on renal function and morphology and on blood pressure in SDT fatty rats. Male SDT fatty rats underwent 1/2 Nx or a sham operation (Sham). Subsequently, animals were studied with respect to renal function and histological alterations. Induction of 1/2 Nx in SDT fatty rats led to functional and morphological damage to the remnant kidney and to hypertension, which are considered main characteristics of chronic kidney disease, at a younger age compared with the sham group. In conclusion, the SDT fatty rat is useful in investigations to elucidate the pathogenesis of human diabetic nephropathy and in new drug discovery.

Gender differences in metabolic disorders and related diseases in Spontaneously Diabetic Torii-Lepr(fa) rats.

The Spontaneously Diabetic Torii Lepr(fa) (SDT fatty) rat is a novel type 2 diabetic model wherein both male and female rats develop glucose and lipid abnormalities from a young age. In this study, we investigated gender differences in abnormalities and related complications in SDT fatty rats. Food intake was higher in males compared to female rats; however, body weight was not different between genders. Progression of diabetes, including increases in blood glucose and declines in blood insulin, was observed earlier in male rats than in females, and diabetic grade was more critical in male rats. Blood lipids tended to increase in female rats. Gonadal dysfunction was observed in both male and female rats with aging. Microangiopathies, such as nephropathy, retinopathy, neuropathy, and osteoporosis, were seen in both genders, and pathological grade and progression were more significant in males. Qualitative and quantitative changes were observed for metabolic disease gender differences in SDT fatty rats. The SDT fatty rat is a useful model for researching gender differences in metabolic disorders and related diseases in diabetes with obesity.

Diabetic complications in obese type 2 diabetic rat models.

We overviewed the pathophysiological features of diabetes and its complications in obese type 2 diabetic rat models: Otsuka Long-Evans Tokushima fatty (OLETF) rat, Wistar fatty rat, Zucker diabetic fatty (ZDF) rat and Spontaneously diabetic Torii (SDT) fatty rat. Pancreatic changes with progression of diabetes were classified into early changes, such as islet hypertrophy and degranulation of ß cells, and degenerative changes, such as islet atrophy and fibrosis of islet with infiltration of inflammatory cells. Renal lesions in tubuli and glomeruli were observed, and nodular lesions in glomeruli were notable changes in OLETF and SDT fatty rats. Among retinal changes, folding and thickening were interesting findings in SDT fatty rats. A decrease of motor nerve conduction velocity with progression of diabetes was presented in obese diabetic rats. Other diabetic complications, osteoporosis and sexual dysfunction, were also observed. Observation of bone metabolic abnormalities, including decrease of osteogenesis and bone mineral density, and sexual dysfunction, including hypotestosteronemia and erectile dysfunction, in obese type 2 diabetic rats have been reported.

Physiological changes induced by salt intake in female Spontaneously Diabetic Torii-Lepr(fa) (SDT fatty) rat, a novel obese type 2 diabetic model.

Salt plays an important role in the control of blood pressure in obesity and diabetes mellitus. In this study, we investigated physiological changes such as blood pressure and renal function in salt-loaded female Spontaneously Diabetic Torii-Lepr(fa) (SDT fatty) rats. SDT fatty rats were given 1% NaCl in drinking water for 14 weeks, from 4 to 18 weeks of age. Significant salt-sensitive hypertension was observed in the salt-loaded SDT fatty rats. Moreover, the salt-loaded rats showed a decrease of creatinine clearance and deterioration on pathological renal findings, including glomerulosclerosis and tubular and interstitial lesions. Female SDT fatty rat is a useful model for investigating the mechanisms of high salt sensitivity in obesity and diabetes mellitus.

Pathophysiological analysis of female Spontaneously Diabetic Torii fatty rats.

Obesity, hyperglycemia, hyperlipidemia, and diabetes-associated complications appear at younger ages (6-8 weeks) in the male Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat than in the male original SDT (SDT-+/+) rat. However, the incidence and progression of diabetes mellitus and diabetic complications in the female SDT-fa/fa rat have not been reported in detail. In the present study, the pathophysiological features of the female SDT-fa/fa rat were examined, and compared with those of the female SDT-+/+ rat. Female SDT-fa/fa rats showed hyperphagia, obesity, hyperglycemia, and hyperlipidemia from 5 or 6 weeks of age, and hyperinsulinemia was observed from 5 to 12 weeks. Pathological changes pancreatic islets were observed from 8 weeks. Renal function parameters, such as urine volume and urinary protein, increased from 16 weeks, and pathological findings in the renal tubule, and cataracts were also observed from 16 weeks. Increases of visceral and subcutaneous fats were obvious during the observation period. In pair-feeding with SDT-+/+ rats, SDT-fa/fa rats showed improved hyperglycemia and hypertriglycemia, but hypercholesterolemia was not entirely improved during the study period. Female SDT-fa/fa rats showed diabetes mellitus and diabetes-associated complications at young ages, and fat accumulation was remarkable. Suppression of hyperphagia in SDT-fa/fa rats was effective at improving hyperglycemia and hypertriglycemia. In conclusion, the female SDT-fa/fa rat has the potential to become an important animal model of type 2 diabetes mellitus with obesity, especially for women, for which few models currently exist.

A novel model of obesity-related diabetes: introgression of the Lepr(fa) allele of the Zucker fatty rat into nonobese Spontaneously Diabetic Torii (SDT) rats.

An fa allele of the leptin receptor gene (Lepr(fa)) of the Zucker fatty rat was introduced into the genome of the Spontaneously Diabetic Torii (SDT) rat, an inbred model of nonobese type 2 diabetes mellitus, through the 'Speed congenic method'. The newly established congenic strain of a SDT rat for Lepr(fa) was maintained by intercrossing between fa-heterozygous littermates, and the phenotypes related to obesity and diabetes were investigated till 32 wks of age. SDT fa/fa rats of both sexes exhibited obesity, adiposity and insulin resistance associated with hyperphagia from the loss of leptin action. Interestingly, they developed diabetes from 5 wks of age in males and 8 wks in females with the incidences reaching 100% at 16 wks in males and 73% at 32 wks in females. In contrast, heterozygous (+/fa) and wild-type (+/+) rats developed spontaneous nonobese diabetes in males from approximately 20 wks, but not in females, as with the original SDT rats. These results indicate that the fa gene accelerates the onset of diabetes in SDT rats by making adiposity and/or insulin resistance as potent risk factors for development of their diabetes. The SDT.Lepr(fa) congenic rat strain is expected to be a novel model of obesity-related diabetes and could be a useful tool for studies of the genetic backgrounds of diabetes in response to fa-induced obesity.