Addressing the role of 11ß-hydroxysteroid dehydrogenase type 1 in the development of polycystic ovary syndrome and the putative therapeutic effects of its selective inhibition in a preclinical model.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common metabolic and endocrine disorder among reproductive-age women, and the leading cause of anovulatory infertility. 11ß-hydroxysteroid dehydrogenases-1 (11ß-HSD1) catalysing the conversion of inactive cortisone to active cortisol plays a crucial role in various metabolic diseases. However, whether 11ß-HSD1 is associated with the pathogenesis of PCOS and whether 11ß-HSD1 can be a treating target of PCOS remain unknown. METHODS: This study was first designed to explore the role of 11ß-HSD1 in PCOS development and the effect of selective 11ß-HSD1 inhibitor administration on PCOS treatment. Follicular fluid and granulosa cells (GCs) were collected from 32 non-PCOS patients and 37 patients with PCOS to measure cortisol and 11ß-HSDs levels. Female Sprague-Dawley rats (3-week-old) were injected with dehydroepiandrosterone (DHEA) to induce PCOS and their ovaries were collected to measure the abundance of corticosterone (CORT) and 11ß-HSDs. To determine the role of 11ß-HSD1 in PCOS development, we overexpressed 11ß-HSD1 in the ovaries of female rats (5-week-old) or knocked down the expression of 11ß-HSD1 in the ovaries from PCOS rats via lentivirus injection. After lentivirus infection, the body weights, ovarian weights, estrous cycles, reproductive hormones and morphology of the ovary were analysed in rats from different experimental groups. Then to figure out the translational potential of the selective 11ß-HSD1 inhibitor in treating PCOS, PCOS rats were treated with BVT.2733, a selective 11ß-HSD1 inhibitor and a cluster of PCOS-like traits were analysed, including insulin sensitivity, ovulatory function and fertility of rats from the Control, PCOS and PCOS+BVT groups. Rat ovarian explants and human GCs were used to explore the effect of CORT or cortisol on ovarian extracellular matrix remodelling. RESULTS: The elevated expression of 11ß-HSD1 contributed to the increased cortisol and corticosterone (CORT) concentrations observed in the ovaries of PCOS patients and PCOS rats respectively. Our results showed that ovarian overexpression of 11ß-HSD1 induced a cluster of PCOS phenotypes in rats including irregular estrous cycles, reproductive hormone dysfunction and polycystic ovaries. While knockdown of ovarian 11ß-HSD1 of PCOS rats reversed these PCOS-like changes. Additionally, the selective 11ß-HSD1 inhibitor BVT.2733 alleviated PCOS symptoms such as insulin resistance (IR), irregular estrous cycles, reproductive hormone dysfunction, polycystic ovaries, ovulatory dysfunction and subfertility. Moreover, we showed that cortisol target ovarian insulin signalling pathway and ovarian extracellular matrix (ECM) remodelling in vivo, in ovarian explants and in GCs. CONCLUSION: Elevated 11ß-HSD1 abundance in ovarian is involved in the pathogenesis of PCOS by impairing insulin signalling pathway and ECM remodelling. Selective inhibition of 11ß-HSD1 ameliorates a cluster of PCOS phenotypes. Our study demonstrates the selective 11ß-HSD1 inhibitor as a novel and promising strategy for the treatment of PCOS.

Discovery of Potent Inhibitors of 11ß-Hydroxysteroid Dehydrogenase Type 1 Using a Novel Growth-Based Protocol of in Silico Screening and Optimization in CONTOUR.

With the continuous progress in ultralarge virtual libraries which are readily accessible, it is of great interest to explore this large chemical space for hit identification and lead optimization using reliable structure-based approaches. In this work, a novel growth-based screening protocol has been designed and implemented in the structure-based design platform CONTOUR. The protocol was used to screen the ZINC database in silico and optimize hits to discover 11ß-HSD1 inhibitors. In contrast to molecular docking, the virtual screening process makes significant improvements in computational efficiency without losing chemical equities through partitioning 1.8 million ZINC compounds into fragments, docking fragments to form key hydrogen bonds with anchor residues, reorganizing molecules into molecular fragment trees using matched fragments and common substructures, and then regrowing molecules with the help of developed intelligent growth features inside the protein binding site to find hits. The growth-base screening approach is validated by the high hit rate. A total of 50 compounds have been selected for testing; of these, 15 hits having diverse scaffolds are found to inhibit 11ß-HSD1 with IC50 values of less than 1 µM in a biochemical enzyme assay. The best hit which exhibits an enzyme IC50 of 33 nM is further developed to a novel series of bicyclic 11ß-HSD1 inhibitors with the best inhibition of enzyme IC50 of 3.1 nM. The final lead candidate exhibits IC50 values of 7.2 and 21 nM in enzyme and adipocyte assays, respectively, displayed greater than 1000-fold of selectivity over 11ß-HSD2 and two other related hydroxysteroid dehydrogenases, and can serve as good starting points for further optimization to develop clinical candidates.

Application of ELISA Technique and Human Microsomes in the Search for 11ß-Hydroxysteroid Dehydrogenase Inhibitors.

The metabolic syndrome is defined by impaired carbohydrate metabolism and lipid disorders and often accompanied by hypertension, all of which will lead to obesity and insulin resistance. Glucocorticoids play a regulatory role in the metabolism of proteins, lipids, and carbohydrates. There is growing evidence for a role of glucocorticoids in the development of the metabolic syndrome. The most important factor that regulates the access of endogenous glucocorticoids to receptors after release of glucocorticoids and their diffusion into the cytoplasm of target cells is the steroid metabolism involving a microsomal enzyme, 11ß-hydroxysteroid dehydrogenase (11ß-HSD). The changes in intracellular glucocorticoid metabolism in the pathogenesis of obesity indicate the participation of modulation by 11ß-HSD1, which may represent a new therapeutic target for the treatment of diseases such as type 2 diabetes, visceral obesity, or atherosclerosis. The aim of our study was to determine the fast and effective method to assess inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase. The material for this study was human liver and kidney microsomes. In this study we used ELISA technique using 96-well microplates coated with antibodies which were specific for analyzed enzymes. The method can quickly and efficiently measure the inhibition of both 11ß-HSD1 and 11ß-HSD2. This method can be used to search for and determine inhibitors of this enzyme. Cortisone and cortisol were used as the substrates for corresponding enzyme assays. Furthermore, 3-N-allyl-2-thiouracil derivatives were used by us for comparison purposes in developing the method, although, due to their structure, those derivatives have not previously been considered as potential inhibitors of 11ß-HSD1. 3-N-Allyl-2-thiouracil derivatives are a group worth considering, because by modifying their structure (e.g., by introducing other substituents into the pyrimidine ring) it will be possible to obtain an increase in the activity of compounds in this regard. In conclusion, this study shows an efficient and fast method of determining inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase.

12ß-Acetyloxyperforatin, a New Limonoid from Harrisonia Perforata.

A new A, D-seco limonoid, named 12-acetyloxyperforatin (1), along with three known ones, were isolated from the leaves of Harrisonia perforata. Their structures were elucidated on the basis of spectroscopic analysis, including extensive NMR techniques and computational modelling. These compounds showed no inhibitory activity against the 11ß-HSD1 enzyme.

11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Development by Lentiviral Screening Based on Computational Modeling.

In this study, rat and human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) have been cloned by lentiviral transduction and expressed by CHO-K1 cells. The results showed that recombinant plasmids contained R11bhsd1 or H11bhsd1 have been constructed, which is consistent with the gene bank respectively. A clone cell was selected with G418 and cultivated to express 11ß-HSD1. 11ß-HSD1 catalytic activity of rat and human were 99.5 and 98.7%, respectively, determined by scanning radiometer. And the cloned CHO-K1 cells expressed the protein of 11ß-HSD1 in a long-term and stable manner, which makes it suitable for screening 11ß-HSD1 inhibitor. The three-dimensional structure of 11ß-HSD1 was used for studying the interaction between inhibitor and enzyme by the binding poses predicted by AutoDock and LeDock software. The docking results revealed that compound 8 forms 2 hydrogen bonds with the residues of Gly-216 and Ile-218 in 11ß-HSD1, that is to say compound 8 maybe a good 11ß-HSD1 inhibitor. Moreover, C57BL/6 mice with R11bHsd1 overexpression had a higher body weight, glucose, total cholesterol, and triglyceride levels compared to the mice treated with an empty viral vector. The results might provide a beneficial foundation for selecting inhibitors of 11ß-HSD1 or for researching drug candidate mechanisms.

Pentacyclic Triterpenes from Cecropia telenitida Can Function as Inhibitors of 11ß-Hydroxysteroid Dehydrogenase Type 1.

Plant extracts from the genus Cecropia have been used by Latin-American traditional medicine to treat metabolic disorders and diabetes. Previous results have shown that roots of Cecropia telenitida contain pentacyclic triterpenes and these molecules display a hypoglycemic effect in an insulin-resistant murine model. The pharmacological target of these molecules, however, remains unknown. Several lines of evidence indicate that pentacyclic triterpenes inhibit the 11ß-hydroxysteroid dehydrogenase type 1 enzyme, which highlights the potential use of this type of natural product as phytotherapeutic or botanical dietary supplements. The main goal of the study was the evaluation of the inhibitory effect of Cecropia telenitida molecules on 11ß-hydroxysteroid dehydrogenase type 1 enzyme activity. A pre-fractionated chemical library was obtained from the roots of Cecropia telenitida using several automated chromatography separation steps and a homogeneous time resolved fluorescence assay was used for the bio-guided isolation of inhibiting molecules. The screening of a chemical library consisting of 125 chemical purified fractions obtained from Cecropia telenitida roots identified one fraction displaying 82% inhibition of the formation of cortisol by the 11ß-hydroxysteroid dehydrogenase type 1 enzyme. Furthermore, a molecule displaying IC50 of 0.95 ± 0.09 µM was isolated from this purified fraction and structurally characterized, which confirms that a pentacyclic triterpene scaffold was responsible for the observed inhibition. Our results support the hypothesis that pentacyclic triterpene molecules from Cecropia telenitida can inhibit 11ß-hydroxysteroid dehydrogenase type 1 enzyme activity. These findings highlight the potential ethnopharmacological use of plants from the genus Cecropia for the treatment of metabolic disorders and diabetes.

Acute anti-obesity effects of intracerebroventricular 11ß-HSD1 inhibitor administration in diet-induced obese mice.

The hypothalamus is the regulatory centre of both appetite and energy balance and endoplasmic reticulum (ER) stress in the hypothalamus is involved in the pathogenesis of obesity. Recently, inhibition of 11 ß hydroxysteroid dehydrogenase type1 (11ß-HSD1) was reported to have an anti-obesity effect by reducing fat mass. However, the link between the role of 11ß-HSD1 in the hypothalamus and obesity has yet to be determined. In the present study, embryonal primary hypothalamic neurones and high-fat diet (HFD) fed mice were used to investigate the anorexigenic effects of 11ß-HSD1 inhibitors both in vitro and in vivo. In hypothalamic neurones, carbenoxolone (a non selecitve 11ß-HSD inhibitor) alleviated ER stress and ER stress-induced neuropeptide alterations. In HFD mice, i.c.v. administration of carbenoxolone or KR67500 (nonselective and selective 11ß-HSD1 inhibitors, respectively) was associated with less weight gain compared to control mice for 24 hours after treatment, presumably by reducing food intake. Furthermore, glucose regulated protein (Grp78), spliced X-box binding protein (Xbp-1s), c/EBP homologous protein (chop) and ER DnaJ homologue protein (Erdj4) expression was decreased in the hypothalami of mice administrated 11ß-HSD1 inhibitors compared to controls. Conversely, the phosphorylation of protein kinase B (PKB/Akt), signal transducer and activator of transcription 3 (Stat3), mitogen-activated protein kinase (MAPK/ERK) and S6 kinase1 (S6K1) in the hypothalamus was induced more in mice treated using the same regimes. In conclusion, acute 11ß-HSD1 inhibition in the hypothalamus could reduce food intake by decreasing ER stress and increasing insulin, leptin, and mammalian target of rapamycin complex 1 (mTORC1) signalling.

Citrinal B, natural 11 beta-hydroxysteroid dehydrogennase type 1 inhibitor identified from structure-based virtual screening.

Citrinal B, a tricyclic compound from endophytic fungus Colletotrichum capsici in our previous studies, exhibited significant inhibitory activity against 11ß-hydroxysteroid dehydrogenase type 1 (11 ß-HSD1) in vitro and showed strong binding affinity to 11ß-HSD1. Moreover, citrinal B treatments decreased the lipid droplet accumulation associate with the inhibition of 11ß-HSD1 expression in differentiate induced 3T3-L1 preadipocytes. Furthermore, the molecular docking demonstrated that citrinal B coordinated in the active site of 11ß-HSD1 is essential for the ability of diminishing the enzyme activity.

Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11ß hydroxysteroid dehydrogenase type 1 inhibitor.

A potent, in vivo efficacious 11ß hydroxysteroid dehydrogenase type 1 (11ß HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11ß HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11ß HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.

16-nor Limonoids from Harrisonia perforata as promising selective 11ß-HSD1 inhibitors.

Two new 16-nor limonoids, harperspinoids A and B (1 and 2), with a unique 7/5/5/6/5 ring system, have been isolated from the plant Harrisonia perforate together with a known one, Harperforin G (3). Their structures were elucidated by NMR spectroscopy, X-ray diffraction analysis and computational modelling. Compound 1 exists as polymorphic crystals. Conformations of 1 in solution were further discussed based on the computational results. These compounds exhibited notable inhibitory activity against the 11ß-HSD1 enzyme. Compound 3 had potencies for the inhibition of human 11ß-HSD1 with high selectivity against 11ß-HSD2 (IC50 0.58 µM, SI > 174). Molecular docking and quantitative structure-activity relationship studies revealed a mixed regulatory mechanism.

Pharmacokinetic characterization of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone, a novel 11ß-hydroxysteroid dehydrogenase type 1 inhibitor in rats.

11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is associated with metabolic syndromes such as type 2 diabetes mellitus and obesity. A new 11ß-HSD1 inhibitor known as 2-(3-benzoyl)-4-hydroxy-1, 1-dioxo-2H-1, 2-benzothiazine-2-yl-1-phenylethanone (KR-66344) is being developed as a therapeutic agent for these metabolic diseases. The purpose of this study was to characterize the pharmacokinetics of KR-66344 to support further preclinical development. KR-66344 showed high liver microsomal stability with T1/2 values >3 h and high permeability with apparent permeability coefficients of 15.2-24.2 × 10(-6) cm/s in Caco-2 cell monolayers. KR-66344 was also strongly bound to plasma proteins (>98%). After intravenous dosing, KR-66344 exhibited low systemic clearance (0.27-0.37 L/h/kg) and a low to moderate volume of distribution at steady state (0.79-0.8 L/kg). The bioavailability and terminal half-lives of KR-66344 following oral administration were 25% and 1.7-3.3 h, respectively. In addition, KR-66344 showed dose-independent pharmacokinetics at 0.5-10 mg/kg in intravenous and oral pharmacokinetic studies.

Effect of palm oil (Elaeis guineensis) tocotrienols on mesenteric adipose tissue deposition and the expression of 11ß-hydroxysteroid dehydrogenase type 1 enzyme (11ß-HSD1) in adrenalectomized rats treated with dexamethasone.

OBJECTIVES: A study was done to investigate the effect of palm oil (Elaeis guineensis) tocotrienols on (1) rats mesenteric adipose tissue deposition (2) and 11ß-HSD1 enzyme expression in mesenteric adipocyte. There is a necessity to find an inhibitor for the 11ß-HSD1 enzyme which enhances the proliferation of mesenteric adipocyte tissue therefore curbing the onset of metabolic syndrome. MATERIAL AND METHODS: A total of 35 male Spraque Dawley rats were divided into 5 different groups, i.e., a baseline control group (n=7), a sham operated group (n=7) and three experimental adrenalectomised groups (ADR) (n=21). Each of the experimental ADR group was given intramuscular dexamethasone (Dexa) with a dose of 120 µg/kg after 2 weeks post adrenalectomy and were divided into adrenalectomised control (n=7), Glycyrrhizic acid (GCA) treated (dose=120 mg/kg/day; n=7) and Palm Tocotrienol treated (dose=60 mg/kg/day; n=7) groups. These various treatments were given 6 days a week for 8 weeks via gastric gavage (following 2 weeks of adrenalectomy). Data is expressed as mean ± standard error mean (SEM), compared to each other using one-way analysis-of-variance (ANOVA) followed by Tukey's post hoc test and then a t-test. RESULTS: The results show that palm tocotrienol tend to slightly increase mesenteric adipose tissue deposition in rats. However, palm tocotrienol was also found to have potential in inhibiting the expression of 11ß-HSD1 enzyme in mesenteric adipocytes. CONCLUSIONS: This study suggests palm tocotrienol inhibits 11ß-HSD1 enzyme expression and activity.

Inhibition of 11ß-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice.

11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) controls the production of active glucocorticoid (GC) and has been proposed as a new target for the treatment of type 2 diabetes. We have previously reported that a natural product, curcumin, exhibited moderate inhibition and selectivity on 11ß-HSD1. By analyzing the models of protein, microsome, cells and GCs-induced mice in vitro and in vivo, this study presented a novel curcumin analog, LG13, as a potent selective 11ß-HSD1 inhibitor. In vivo, Type 2 diabetic mice were treated with LG13 for 42 days to assess the pharmacological benefits of 11ß-HSD1 inhibitor on hepatic glucose metabolism. In vitro studies revealed that LG13 selectively inhibited 11ß-HSD1 with IC50 values at nanomolar level and high selectivity over 11ß-HSD2. Targeting 11ß-HSD1, LG13 could inhibit prednisone-induced adverse changes in mice, but had no effects on dexamethasone-induced ones. Further, the 11ß-HSD1 inhibitors also suppressed 11ß-HSD1 and GR expression, indicating a possible positive feedback system in the 11ß-HSD1/GR cycle. In type 2 diabetic mice induced by high fat diet plus low-dosage STZ injection, oral administration with LG13 for 6 weeks significantly decreased fasting blood glucose, hepatic glucose metabolism, structural disorders, and lipid deposits. LG13 exhibited better pharmacological effects in vivo than insulin sensitizer pioglitazone and potential 11ß-HSD1 inhibitor PF-915275. These pharmacological and mechanistic insights on LG13 also provide us novel agents, leading structures, and strategy for the development of 11ß-HSD1 inhibitors treating metabolic syndromes.

A combination of probiotics and whey proteins enhances anti-obesity effects of calcium and dairy products during nutritional energy restriction in aP2-agouti transgenic mice.

Lactobacillus rhamnosus GG, Lactobacillus paracasei TMC0409, Streptococcus thermophilus TMC1543 and whey proteins were used to prepare fermented milk. For the experiment aP2- agouti transgenic mice were pre-treated with a high-sucrose/high-fat diet for 6 weeks to induce obesity. The obese mice were fed a diet containing 1·2% Ca and either non-fat dried milk (NFDM) or probiotic-fermented milk (PFM) with nutritional energy restriction for 6 weeks. The animals were examined after the treatment for changes in body weight, fat pad weight, fatty acid synthase (FAS) activity, lypolysis, the expression levels of genes related to lipid metabolism, insulin sensitivity in adipocytes and skeletal muscle and the presence of biomarkers for oxidative and inflammatory stress in plasma. It was found that the PFM diet significantly reduced body weight, fat accumulation, and adipocyte FAS activity, and increased adipocyte lipolysis as compared with the effects of the NFDM diet (P<0·05). The adipose tissue gene expression of 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) was significantly suppressed in mice that were fed PFM as compared with those that were fed NFDM (P<0·05). PFM caused a greater up-regulation of skeletal muscle PPARα, PPARδ, uncoupling protein 3 (UCP3) and GLUT4 expression and a significant decrease in the plasma concentration of insulin, malondialdehyde, TNF-α, monocyte chemotactic protein-1 and C-reactive protein as compared with the effects of NFDM (P<0·05). Fermentation of milk with selected probiotics and supplementation of milk with whey proteins may thus enhance anti-obesity effects of Ca and dairy products by the suppression of adipose tissue lipogenesis, activation of fat oxidation in skeletal muscle and reduction of oxidative and inflammatory stress.

Pistacia lentiscus Oleoresin: Virtual Screening and Identification of Masticadienonic and Isomasticadienonic Acids as Inhibitors of 11ß-Hydroxysteroid Dehydrogenase 1.

In traditional medicine, the oleoresinous gum of Pistacia lentiscus var. chia, so-called mastic gum, has been used to treat multiple conditions such as coughs, sore throats, eczema, dyslipidemia, and diabetes. Mastic gum is rich in triterpenes, which have been postulated to exert antidiabetic effects and improve lipid metabolism. In fact, there is evidence of oleanonic acid, a constituent of mastic gum, acting as a peroxisome proliferator-activated receptor γ agonist, and mastic gum being antidiabetic in mice in vivo. Despite these findings, the exact antidiabetic mechanism of mastic gum remains unknown. Glucocorticoids play a key role in regulating glucose and fatty acid metabolism, and inhibition of 11ß-hydroxysteroid dehydrogenase 1 that converts inactive cortisone to active cortisol has been proposed as a promising approach to combat metabolic disturbances including diabetes. In this study, a pharmacophore-based virtual screening was applied to filter a natural product database for possible 11ß-hydroxysteroid dehydrogenase 1 inhibitors. The hit list analysis was especially focused on the triterpenoids present in Pistacia species. Multiple triterpenoids, such as masticadienonic acid and isomasticadienonic acid, main constituents of mastic gum, were identified. Indeed, masticadienonic acid and isomasticadienonic acid selectively inhibited 11ß-hydroxysteroid dehydrogenase 1 over 11ß-hydroxysteroid dehydrogenase 2 at low micromolar concentrations. These findings suggest that inhibition of 11ß-hydroxysteroid dehydrogenase 1 contributes to the antidiabetic activity of mastic gum.

Hupehenols A-E, selective 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors from Viburnum hupehense.

Five selective 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) competitive inhibitors, hupehenols A-E (1-5), were isolated from Viburnum hupehense. The structure elucidation indicated that compounds 1-5 are new 20,21,22,23,24,25,26,27-octanordammarane triterpenoids. Their structures were established on the basis of NMR spectroscopic and mass spectrometric analysis. Hupehenols A-E (1-5) showed inhibition against human 11ß-HSD1, with hupehenols B (2) and E (5) having IC50 values of 15.3 and 34.0 nM, respectively. Moreover, hupehenols C (3) and D (4) are highly selective inhibitors of human 11ß-HSD1 when compared to murine 11ß-HSD1.

Pharmacological characterization of the selective 11ß-hydroxysteroid dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes.

To combat the increased morbidity and mortality associated with the developing diabetes epidemic new therapeutic interventions are desirable. Inhibition of intracellular cortisol generation from cortisone by blocking 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. A challenge in developing 11ß-HSD1 inhibitors has been the species selectivity of small molecules, as many compounds are primate specific. Here we describe our strategy to identify potent selective 11ß-HSD1 inhibitors while ensuring target engagement in key metabolic tissues, liver and fat. This strategy enabled the identification of the clinical candidate, BI 135585.

Discovery of pyridyl sulfonamide 11-beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors for the treatment of metabolic disorders.

A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11ß-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability.

Lithocarpic Acids A-N, 3,4-seco-Cycloartane Derivatives from the Cupules of Lithocarpus polystachyus.

Fourteen new 3,4-seco-cycloartane-type triterpenes, lithocarpic acids A-N (1-14), together with one known compound, coccinetane E (15), were identified from the cupules of Lithocarpus polystachyus. The structures of 1-14 were determined by spectroscopic data analysis and chemical methods, and the absolute configurations of 1 and 4 were defined unequivocally by X-ray crystallography using Cu Kα radiation. Compounds 1-15 are the first examples of 3,4-seco-cycloartane derivatives isolated from the genus Lithocarpus. Among them, compounds 1 and 2, 9 and 10, and 11 and 12 were found to be three pairs of C-24 epimers, while compounds 7 and 8 represent the first examples of 3,4-seco-norcycloartane-type triterpenes. Compound 1, as the major component of the plant extract, showed potent antibacterial activity against Micrococcus luteus and Bacillus subtilis, with MIC values of 3.1 and 6.3 µg/mL, respectively, as well as inhibitory activity against human and mouse 11ß-hydroxysteroid dehydrogenase type 1, with IC50 values of 1.9 and 0.24 µM, respectively.

[Terpenoids and sterols from Ricinus communis and their activities against diabetes].

Seven terpenoids and three sterols were isolated from the methanol extracts of the aerial parts of Ricinus communis by chromatography methods and their structures were identified by spectra analysis as ficusic acid( 1), phytol(2), callyspinol(3) , lupeol(4), 30-norlupan-3beta-ol-20-one(5) , lup-20(29)-en-3beta,15alpha-diol(6) , acetylaleuritolic acid( 7), stigmast4-en-3-one(8) , stig-mast-4-en-6beta-ol-3-one(9) , and stigmast4-en-3,6-dione(10). Compounds 1-3 and 5-10 were obtained from this species for the first time and 5 and 6 showed significant inhibitive activity and good selectivity against 11beta-HSD of mouse and human in vitro. [Key words] Ricinus communis; terpenoids; sterols; 11beta-HSD