Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore

Synthesis and structure–activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF₃ group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.     

Description of the oöcysts of Eimeria septemvittata n. sp. (Apicomplexa: Eimeriidae) from queen snakes,Regina septemvittata (Serpentes: Colubridae), in Arkansas

Coccidian oöcysts recovered from the feces of queen snakes, Regina septemvittata, from Arkansas, USA, were found to represent a previously unreported eimerian. Oöcysts of Eimeria septemvittata n. sp. are spherical or subspherical, 14.6×14.0 (12–16×12–15) μm, with a thin, bi-layered wall; the shape-index (length/width) is 1.04 (1.00–1.17). The micropyle and oöcyst residuum are absent but a large polar granule is present. The sporocysts are ovoidal, 11.3×5.6 (9.5–13.5×5–6) μm and possess a Stieda body; the shape-index is 2.02 (1.81–2.50). Each sporozoite contains a large, centrally located refractile body and a generally smaller, posterior refractile body.     

One Month Weight Loss Predicts the Efficacy of Liraglutide in Obese Patients: Data from A Single Center

Objective: Liraglutide is a glucagon-like peptide 1 receptor agonist which acts through peripheral and central receptor pathways affecting food intake. Preliminary identification of responder patients represents a crucial point to reduce an inappropriate exposure to the drug and the health expenditure. The primary endpoint of our study was to identify predictors of liraglutide efficacy in the short term follow-up. The secondary endpoint was to evaluate the treatment efficacy stratified by the underlying psychiatric disorder.Methods: We evaluated a cohort of 100 patients (77 females, 23 males, mean body mass index 38.6 ± 3.2 kg/m²) who were evaluated at baseline, and after 1, 3, and 6 months of treatment. Liraglutide efficacy was defined by a weight loss ≥5% of initial weight. Sociodemographic/metabolic parameters, food intake, smoking habit, and physical activity were correlated with liraglutide efficacy.Results: There was a significant weight loss after 1 month of therapy, as well as after 3 and 6 months when compared to the baseline (P<.0001; 27%, 45%, and 57% of patients showed a weight loss ≥5%, respectively). No difference was found in weight loss between the 3 groups of patients (with binge eating, with/without psychiatric disorders). The weight loss at 1 month was the only predictor of a positive response to the treatment.Conclusion: Our results confirm the efficacy of liraglutide even at a lower dose than conventional. The early response to the drug seems to be a good predictor of long-term efficacy and it might be useful in clinical practice to identify patients in whom liraglutide may induce a significant weight loss.Abbreviations: BMI = body mass index; EMA = European Medicine Agency; FDA = Food and Drug Administration; GLP-1 RA = glucagon-like peptide 1 receptor agonist     

A multiciliate ‘starcell’ in the parenchyma of the larva of Austramphilina elongata (Amphilinidea)

Rohde K. and Garlick P. R. 1985. A multicilite ‘starcell’ in the parenchyma of the larva of Austramphilina elongata (Amphilinidea). International Journal for Parasitology15: 403–407. The ultrastructure of a new cell type is described. It is located at the posterior end of the penetration glands of larval Austramphilina. Large numbers of cilia of the cell protrude in all directions into adjacent fluidfilled spaces. The cell is rich in mitochondria and has a cavity which is separated from the surrounding tissue spaces by a sheath of cytoplasm and by ribs of cytoplasm with a membrane between them. Leptotriches project from the cell body into the cavity. Possible functions of the cell are discussed.     

Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. Part 9: Synthesis,characterization and molecular modeling of pyridinyl isosteres of N-BPE-8-CAC (1), a high affinity ligand for opioid receptors

Derivatives of the lead compound N-BPE-8-CAC (1) where each CH of the biphenyl group was individually replaced by N were prepared in hopes of identifying high affinity ligands with improved aqueous solubility. Compared to 1, binding affinities of the five possible pyridinyl derivatives for the μ opioid receptor were between threefold lower to fivefold higher with the K_i of the most potent compound being 0.064 nM. Docking of 8-CAC (2) into the unliganded binding site of the mouse μ opioid receptor (pdb: 4DKL) revealed that 8-CAC and β-FNA (from 4DKL) make nearly identical interactions with the receptor. However, for 1 and the new pyridinyl derivatives 4–8, binding is not tolerated in the 8-CAC binding mode due to the steric constraints of the large N-substituents. Either an alternative binding mode or rearrangement of the protein to accommodate these modifications may account for their high binding affinity.     

Ultrastructural study of the male gamete of Glossobothrium sp. (Cestoda: Bothriocephalidea: Triaenophoridae) a parasite of Schedophilus velaini (Perciformes: Centrolophidae) in Senegal

This paper describes the ultrastructure of the male gamete of Glossobothrium sp. (Bothriocephalidea: Triaenophoridae). The mature spermatozoon of Glossobothrium sp. is filiform and possesses two axonemes, a single helicoidal crested body, a parallel nucleus, parallel cortical microtubules and granules of glycogen. In Glossobothrium sp. we describe for first time a 200-250 nm thick crest-like body in the Bothriocephalidean. The anterior part of the spermatozoon exhibits a ring of 27 electron-dense cortical microtubules encircling the first axoneme. This structure persists until the appearance of the second axoneme. When the ring of electron-dense cortical microtubules disappears, the spermatozoon exhibits two bundles of thin cortical microtubules. The posterior part of the spermatozoon contains the posterior extremity of the second axoneme, the posterior extremity of the nucleus and few cortical microtubules. Soon nucleus disappears and the axoneme is disorganized. Thus the posterior extremity of the spermatozoon of Glossobothrium sp. exhibits only singlets produced by the disorganization of the doublets of the second axoneme and few cortical microtubules. This type of posterior extremity of the mature spermatozoon has never been described previously in the Triaenophoridae.     

Larval adipose tissue of homoeotic bithorax mutants of Drosophila.

In the homoeotic bithorax mutant combination bx³$\text{pbx}\text{Ubx}{}^{105}$ of Drosophila melanogaster, the metathoracic segment is transformed to a mesothoracic segment and the adult flies have an extra pair of wings in place of the paired halteres [Lewis, E. B. (1963). Amer. Zool.3, 33–56]. The morphology of the larval fat body, the number of cells in the fat body, and the distribution pattern of kynurenine autofluorescent materials (KAF+) in this tissue were compared in the homoeotic mutant and a wild-type strain. The mutant has an additional mass of adipose cells anterior to the posterior margin of the ventral commissure of the fat body. However, the total number of adipose cells in the two strains as well as the limits of the KAF+ cell population do not differ. Therefore, the bithorax transformation in the larval fat body involves rearrangement of the same cell population as that in the normal strain. This study suggests (1) that the bithorax mutant genes affect the pattern of cell segregation and/or migration of preblastoderm nuclei during embryogenesis and (2) that the larval fat body of Drosophila has a segmental origin.     

Adiposity-Related Cancer and Functional Imaging of Brown Adipose Tissue

Objective: Brown adipose tissue (BAT) is involved in energy dissipation and cytokine production and is potentially beneficial for the human body. The aim of the paper is to review the literature on adiposity-related cancer and functional imaging of BAT.Methods: We performed a review on adiposity-related cancer and functional imaging of BAT. We extensively researched papers for information on BAT molecular biology, as well as functional imaging modalities.Results: Adipose tissue is linked to the development of many cancers. Multiple drugs including fenofibrate, spironolactone, and other substances, as well as experimental agents like β-3 receptor agonists, caffeine, green tea extract, medium chain triglycerides (MCTs), and adenosine are known to stimulate and activate BAT. However, cold and nonshivering thermogenesis are the main activators of BAT. BAT has been detected on both magnetic resonance imaging (MRI) and 18F-fluorodexoxyglucose positron emission tomography (18F-FDG-PET)-based imaging in multiple studies. Different methods of cold stimulation and static and dynamic protocols have been used to detect and image BAT. Factors like sex, fasting or fed state, surface skin temperature, and/or body mass index (BMI) may influence PET-based BAT detection. BAT has also been detected using MRI, ^99mTechnetium(Tc)-sestamibi, and 123I- metaiodobenzylguanidine single-photon emission computed tomography/computed tomography (MIBG SPECT/CT).Conclusions: Stimulation of BAT offers promise in the management of obesity-related conditions. Tracers like &lsqb;¹⁵O]-H₂O, &lsqb;¹¹C] acetate, and 18F-fluoro-6-thia-heptadecanoic acid (18F-FTHA) that measure BAT blood flow, oxygen utilization, and nonessential fatty acid (NEFA) uptake, respectively, have been studied in humans. Future studies should focus on BAT tissue generation by altering the genetic pathways of adiposity-linked genes.Abbreviations: BAT = brown adipose tissue BMI = body mass index CT = computed tomography 18F-FDG = 18F-fluorodexoxyglucose 18F-FTHA = 18F-fluoro-6- thia-heptadecanoic acid GLUT = glucose transporter MIBG = metaiodobenzylguanidine MRI = magnetic resonance imaging PET = positron emission tomography PPAR = peroxisome proliferator-activated receptor SPECT = single-photon emission computed tomography SUV = standard uptake value Tc = technetium UCP-1 = uncoupling protein 1 WAT = white adipose tissue     

Identifying new lead structures to enhance tolerance towards drought stress via high-throughput screening giving crops a quantum of solace

Novel synthetic lead structures interacting with RCAR/(PYR/PYL) receptor proteins were identified based on the results of a high-throughput screening campaign of a large compound library followed by focused SAR studies of the three most promising hit clusters. Whilst indolinylmethyl sulfonamides 8y,z and phenylsulfonyl ethylenediamines 9y,z showed strong affinities for RCAR/ (PYR/PYL) receptor proteins in wheat, thiotriazolyl acetamides 7f,s exhibited promising efficacy against drought stress in vivo (wheat, corn and canola) combined with confirmed target interaction in wheat and arabidopsis thaliana. Remarkably, binding affinities of several representatives of 8 and 9 were on the same level or even better than the essential plant hormone abscisic acid (ABA).     

Discovery of a 7-arylaminobenzimidazole series as novel CRF1 receptor antagonists

A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF₁) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF₁ receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF₁ receptor and human CRF₁ receptor antagonistic activity (IC₅₀ = 27 nM, 56 nM, respectively). This compound exhibited ex vivo ¹²⁵I-Tyr⁰ (¹²⁵I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20 mg/kg after oral administration. In this report, we discuss the structure–activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method.     

Treatment With Cinacalcet Increases Plasma Adiponectin Concentration in Hemodialyzed Patients With Chronic Kidney Disease and Secondary Hyperparathyroidism

Objective: Cinacalcet increases calcium-sensing receptor (CaSR) sensitivity to serum calcium. CaSR is expressed by adipocytes, and adiponectin is an adipokine with antiatherogenic and insulin-sensitizing properties. The aim of this study was to assess the influence of a 3-month cinacalcet regimen on plasma adiponectin concentration in hemodialyzed patients (HDP) with chronic kidney disease (CKD) and secondary hyperparathyroidism (sHPT).Methods: Plasma adiponectin, advanced oxidation protein products (AOPP), serum interleukin-6 (IL-6) and C-reactive protein (CRP) concentrations were assessed in 65 HDP with sHPT treated with cinacalcet (30–120 mg/day) before the first dose and after 3 months of treatment.Results: There was a significant decrease in serum parathyroid hormone (PTH) concentration: from 1,089 (891–1,286) pg/mL to 775 (574–976) pg/mL after 3 months of treatment (P<.0001). The treatment was associated with a significant (P = .048) increase in plasma adiponectin concentration from 16.9 (14.4–19.5) μg/mL to 17.8 (15.0–20.6) μg/mL. Significant (P = .03) reduction of plasma AOPP concentration was observed from 186.7 (156.7–216.7) pg/mL to 162.6 (141.2–183.9) pg/mL.Conclusions: A 3-month cinacalcet regimen increased plasma adiponectin concentrations in HDP with sHPT. Increased adiponectinemia in these patients may be related to reduced oxidative stress.Abbreviations: AOPP = advanced oxidation protein products BMI = body mass index CaSR = calcium-sensing receptor CKD = chronic kidney disease CRP = C-reactive protein HDP = hemodialyzed patient IL = interleukin PTH = parathyroid hormone sHPT = secondary hyperparathyroidism     

The Benefit of Short-Term Weight Loss with Anti-Obesity Medications in Real-World Clinical Practice

Objective: The effectiveness of anti-obesity medications (AOMs) outside of clinical trials is unclear. The objective of this study was to compare the short-term effectiveness of AOMs in real-world practice.Methods: This retrospective study included adults aged ≥18 years, with body mass index ≥30 kg/m² or ≥27 kg/m² with at least one obesity-related comorbidity who were prescribed phentermine hydrochloride, phenterminetopiramate, bupropion-naltrexone, or lorcaserin for 12 consecutive weeks between 2006 and 2016 at a large tertiary healthcare system. Propensity score–matched cohorts were created for each pair of AOMs. The primary outcomes were percent and absolute weight loss from baseline after 12 weeks. A prediction model was constructed to estimate weight loss with different AOMs based on demographic and clinical data.Results: Of the 3,411 patients included in this study, patients lost an average of 3.45% of body weight from baseline. All AOMs were associated with a significant weight loss from baseline (P<.0001). Patients lost the highest percentage of body weight on phentermine hydrochloride (3.75 ± 5.66%), followed by phentermine-topiramate (3.63 ± 5.7%), bupropion-naltrexone (2.66 ± 5.03%), and lorcaserin (1.84 ± 6.69%). In propensity-matched cohorts, patients taking phentermine hydrochloride lost more weight than those taking lorcaserin or bupropion-naltrexone, and patients taking phentermine topiramate lost more weight than patients taking lorcaserin.Conclusion: In real-world practice, AOMs are associated with clinically meaningful weight loss of 2 to 4% after 12 weeks. In this study, phentermine hydrochloride and phentermine topiramate produced the most weight loss. AOMs should be seriously considered as part of the armamentarium to treat patients with obesity.Abbreviations: AOM = anti-obesity medication; BMI = body mass index; EMR = electronic medical record; FDA = Food and Drug Administration; T2D = type 2 diabetes     

Hashimoto Thyroiditis not Associated with Vitamin D Deficiency

Objective: Vitamin D deficiency is associated with several autoimmune diseases. This study assessed whether vitamin D deficiency is associated with Hashimoto thyroiditis (HT).Methods: Two groups of patients were selected for which serum 25-hydroxyvitamin D (25(OH)D) levels had been measured: (1) a study group of patients diagnosed with HT as indicated by thyroid antibodies, and (2) a healthy control group. Each group was separated by sex and then controlled for age and body mass index (BMI). Groups' mean 25(OH)D levels were compared by analysis of variance (ANOVA), and percent frequencies of vitamin D sufficiency, insufficiency, and deficiency were compared with a Z-test. The correlations between 25(OH)D levels and thyroid antibodies and thyroid-stimulating hormone (TSH) levels were also tested.Results: The mean 25(OH)D levels for the HT and control groups were significantly different in females (30.75 vs. 27.56 ng/mL, respectively) but not in males (14.24 vs. 13.26 ng/mL). HT females had a higher rate of vitamin D sufficiency (51.7% vs. 31.1%) and a lower rate of insufficiency (48.3% vs. 68.9%) relative to control females. No such differences were found in the male groups. None of the females were vitamin D deficient, but almost all males were. A significant (P = .016) positive correlation (r_s = 0.436) between 25(OH)D and TPOAb was observed in males.Conclusion: HT is not associated with higher rates of vitamin D deficiency relative to a control group.Abbreviations:BMI = body mass indexHT = Hashimoto thyroiditis25(OH)D = 25-hydroxyvitamin DTgAb = thyroglobulin antibodyTSH = thyroid-stimulating hormoneTPOAb = thyroid-peroxidase antibodyVDR = Vitamin D receptor     

Pathogenesis of Cushing Disease: An Update on the Genetics of Corticotropinomas

Objective: Cushing disease is a rare severe condition caused by pituitary tumors that secrete adrenocorticotropic hormone (ACTH), leading to excessive endogenous glucocorticoid production. Tumors causing Cushing disease, also called corticotropinomas, are typically monoclonal neoplasms that mainly occur sporadically.Methods: Literature review.Results: Cushing disease is very rarely encountered in genetic familial syndromes. Oncogenes and tumor suppressor genes commonly associated with other tumor types are only rarely mutated in this tumor type. The advent of next-generation sequencing led to the identification of a single mutational hotspot in the ubiquitin-specific protease 8 (USP8) gene in almost half of Cushing disease tumors.Conclusion: The new discoveries showcase a novel mechanism responsible for corticotroph tumorigenesis and ACTH hypersecretion and highlight USP8 and its downstream signaling pathways as potential promising pharmacologic targets for the management of Cushing disease.Abbreviations: ACTH = adrenocorticotropic hormone; BRG1 = Brahma-related gene 1; CABLES1 = CDK5 and ABL1 enzyme substrate 1; CD = Cushing disease; CNC = Carney complex; DICER1 = cytoplasmic endoribonuclease III; EGFR = epidermal growth factor receptor; GR = glucocorticoid receptor; IL = interleukin; MEN = multiple endocrine neoplasia; miRNA = microRNA; POMC = proopiomelanocortin; SSTR = somatostatin receptor; USP8 = ubiquitin-specific protease 8     

Comparison Of The Long-Term Effects Of Liraglutide And Glimepiride Monotherapy On Bone Mineral Density In Patients With Type 2 Diabetes

Objective: Patients with type 2 diabetes have an increased risk of fragility fractures; the cause is unclear but is likely multifactorial. Some diabetes treatments induce bone loss, accentuating underlying skeletal fragility and increasing fracture risk. This subgroup analysis aimed to compare long-term effects of liraglutide and glimepiride on bone mineral density (BMD) in patients with type 2 diabetes.Methods: LEAD-3, a 52-week, double-blind, activecontrol, phase III, multicenter trial, investigated the efficacy of liraglutide (1.2 and 1.8 mg/day) versus glimepiride monotherapy in type 2 diabetes. A 52-week, open-label extension followed, in which participants remained on randomized therapy. A subgroup of participants underwent BMD measurement by dual-energy X-ray absorptiometry at baseline, 52, and 104 weeks. The main outcome measure was change from baseline in total body BMD at 52 and 104 weeks, assessed by analysis of covariance.Results: A total of 746 patients with type 2 diabetes aged 19 to 79 years were randomized into the main trial. Of these, 61 patients (20 assigned to liraglutide 1.8 mg/day, 23 to liraglutide 1.2 mg/day, 18 to glimepiride 8 mg/day) had BMD measurements. Baseline age, body mass index, diabetes duration, glycated hemoglobin, and total BMD were similar across treatment groups. There was no apparent difference in mean total BMD change from baseline in patients receiving liraglutide 1.8 or 1.2 mg/day or glimepiride 8 mg/day at 52 or 104 weeks.Conclusion: In this small subgroup analysis, liraglutide monotherapy did not negatively affect total BMD in a 2-year prospective study, suggesting it may not exacerbate the consequences of bone fragility.Abbreviations:BMD = bone mineral densityBMI = body mass indexDPP-4 = dipeptidyl peptidase-4DXA = dual-energy X-ray absorptiometryGLP-1RA = glucagon-like peptide 1 receptor agonistLEAD = Liraglutide Effect and Action in DiabetesTZD = thiazolidinedione     

Efficacy and Safety of Iglarlixi in Hispanics and Non-Hispanic Whites with Type 2 Diabetes

Objective: Type 2 diabetes (T2D) is more common in Hispanic than non-Hispanic white (NHW) populations worldwide, and ethnicity, among other factors, may affect response to therapy. The efficacy and safety of insulin glargine 100 units/mL (iGlar) and the fixed-ratio combination of iGlar and the glucagon-like peptide 1 receptor agonist lixisenatide (iGlarLixi) was assessed in Hispanic and NHW patients with T2D from 25 countries.Methods: In this post hoc analysis, data from two 30-week randomized controlled trials comparing iGlar and iGlarLixi in patients with T2D uncontrolled on basal insulin ± oral antidiabetes drugs (OADs; LixiLan-L: NCT02058160) or uncontrolled on metformin ± OADs (LixiLan-O: NCT02058147) were evaluated.Results: Of the 1,512 patients included across trials, 301 were Hispanic and 1,211 NHW. Compared with iGlar, iGlarLixi resulted in greater reductions in glycated hemoglobin (A1C) and 2-hour postprandial glucose and a higher proportion of patients at target A1C <7.0% (<53 mmol/mol), regardless of ethnicity. Among NHWs from the LixiLan-L trial, documented symptomatic hypoglycemia (plasma glucose ≤70 mg/dL) rates were higher with iGlar compared with iGlarLixi (P = .06), whereas this trend was reversed among Hispanics (P = .07). Nevertheless, in both trials, a greater proportion of patients taking iGlarLixi than iGlar reached the composite efficacy endpoints of target A1C without hypoglycemia and target A1C without weight gain, regardless of ethnicity.Conclusion: These results indicate that iGlarLixi is a viable therapeutic option for both Hispanic and NHW patients with T2D, as it is efficacious without a significant increase in hypoglycemia, irrespective of ethnicity.Abbreviations: A1C = glycated hemoglobin; BMI = body mass index; FPG = fasting plasma glucose; FRC = fixed-ratio combination; GLP-1 RA = glucagon-like peptide 1 receptor agonist; HDL-C = high-density-lipoprotein cholesterol; iGlar = insulin glargine; iGlarLixi = insulin glargine + lixisenatide; LDL-C = low-density-lipoprotein cholesterol; NHW = non-Hispanic white; OAD = oral antidiabetes drug; PPG = postprandial glucose; T2D = type 2 diabetes