Canagliflozin Increases Postprandial Total Glucagon-Like Peptide-1 Levels in the Absence of α-Glucosidase Inhibitor Therapy in Patients with Type 2 Diabetes: A Single-Arm, Non-Randomized, Open-Label Study.

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AST-120 Treatment Alters the Gut Microbiota Composition and Suppresses Hepatic Triglyceride Levels in Obese Mice

Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide. The existence of a relationship between the microbiota and the pathology of hepatic steatosis is also becoming increasingly clear. AST-120, an oral spherical carbon adsorbent, has been shown to be useful for delaying dialysis initiation and improving uremic symptoms in patients with chronic kidney disease. However, little is known about the effect of AST-120 on fatty liver. Methods: AST-120 (5% w/w) was administrated to 6-week-old male db/db mice for 8 weeks. The body weight, blood glucose and food consumption were examined. Hepatic triglyceride (TG) levels, lipid droplets and epididymal fat cell size were measured. The gut microbiota compositions were investigated in feces and cecum. Results: Significant decreases of the hepatic weight and hepatic TG levels were observed in the AST-120-treated db/db mice. Furthermore, AST-120 treatment was also associated with a decrease of Bacteroidetes, increase of Firmicutes, and a reduced ratio of Bacteroidetes to Firmicutes (B/F ratio) in the feces in the db/db mice. The B/F ratio in the feces was correlated with the liver weight and area of the liver occupied by lipid droplets in the db/db mice. Conclusions: These data suggest that AST-120 treatment alters the composition of the fecal microbiota and suppresses hepatic TG levels in the db/db mice.</p

<i>In vitro</i> Inhibition of Recombinant ATX/ENPP2.

<p>ATX = Autotaxin; ENPP2 = ectonucleotide pyrophosphatase/phosphodiesterase 2.</p

LPA Stimulate the Contraction of Isolated Rat Urethra.

<p>The increases in contractile force of isolated rat urethra treated with 18:3-LPA or phenylephrine added to the Magnus apparatus are shown relative to the results for phenylephrine at 100 µM (100%). Results are mean ± S.D. for four urethral specimens.</p

A Novel Highly Potent Autotaxin/ENPP2 Inhibitor Produces Prolonged Decreases in Plasma Lysophosphatidic Acid Formation <i>In Vivo</i> and Regulates Urethral Tension

<div><p>Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 <i>in vivo</i>. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation.</p><p>The IC₅₀ values of ONO-8540506 for lysophospholipase D activity were 6.4–19 nM for recombinant autotaxin/ENPP2 proteins and 4.7–11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration.</p><p>Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia.</p></div

ONO-8430506 regulates <i>in vivo</i> Rat Urethral Tension.

<p>Male SD rats were anesthetized with urethane and the vehicle, tamsulosin (α₁-blocker), or ONO-8430506 were administered intraduodenally. The histograms show the maximum percent decreases (%) in IUP (A and B) and maximum percent decreases in mean blood pressure (C and D) during 20-min after intraduodenal administration of each drug. Results are means ± S.E. for nine or ten rats per group. Comparisons between the treatment groups and vehicle control group were performed using the Dunnett's tests or Student's <i>t</i> tests. ## p<0.01; ### p<0.001 by Student's <i>t</i> test vs Vehicle. ** p<0.01, *** p<0.001 Dunnett test vs Vehicle. $<0.05 by Student's <i>t</i> test vs Tam 0.3. A correlation between the relative inhibition (vs. vehicle control) of plasma LysoPLD activity (%) by the compound and the decreases in IUP (%) at 20 min after intraduodenal administration are shown (E).</p

<i>In vitro</i> Inhibition of Plasma LysoPLD Activity.

<p>LysoPLD = lysophospholipase D.</p><p>IC₅₀ values of ONO-8430506 and other inhibitors for recombinant human ATX/ENPP2 when a synthetic fluorescent substrate (FS-3) or a biological substrate (16:0-LPC) was used are shown for (A). IC₅₀ values of ONO-8430506 for recombinant ATX/ENPP2 protein enzyme activity and LysoPLD activity in plasma samples from various species when incubated in the presence of a biological substrate 16:0-LPC are shown for (B). When 16:0-LPC was used as a substrate, the enzyme activity was determined based on the amount of choline generated. The IC₅₀ values means ± S.D. of three independent experiments.</p

Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist

Overactivation of the mineralocorticoid receptor (MR) is involved in many diseases, such as hypertension, kidney disease, and heart failure. Thus, MR antagonists (MRAs) are expected to be beneficial to patients with these diseases. In order to identify novel nonsteroidal MRAs that overcome the issues of already marketed steroidal MRAs, we searched for new compounds guided by our hypothesis that T-shaped compounds with a hydrophobic core structure, two polar functional groups at both extremities able to interact with MR, and a bulky substituent that can interfere with the folding of the C-terminal helix 12 may exhibit antagonist activity toward MR. We discovered that the novel 1,4-benzoxazin-3-one derivative 19 (apararenone: MT-3995) acted as a highly selective and potent nonsteroidal MRA. Apararenone exhibited a more potent antihypertensive and organ-protective activity than steroidal MRA eplerenone in a primary aldosteronism rat model obtained by infusing aldosterone in uninephrectomized rats

Discovery of Apararenone (MT-3995) as a Highly Selective, Potent, and Novel Nonsteroidal Mineralocorticoid Receptor Antagonist

Overactivation of the mineralocorticoid receptor (MR) is involved in many diseases, such as hypertension, kidney disease, and heart failure. Thus, MR antagonists (MRAs) are expected to be beneficial to patients with these diseases. In order to identify novel nonsteroidal MRAs that overcome the issues of already marketed steroidal MRAs, we searched for new compounds guided by our hypothesis that T-shaped compounds with a hydrophobic core structure, two polar functional groups at both extremities able to interact with MR, and a bulky substituent that can interfere with the folding of the C-terminal helix 12 may exhibit antagonist activity toward MR. We discovered that the novel 1,4-benzoxazin-3-one derivative 19 (apararenone: MT-3995) acted as a highly selective and potent nonsteroidal MRA. Apararenone exhibited a more potent antihypertensive and organ-protective activity than steroidal MRA eplerenone in a primary aldosteronism rat model obtained by infusing aldosterone in uninephrectomized rats

Pharmacokinetics and Pharmacodynamics of the Inhibitor in Rats.

<p>Blood was collected at various time points after single oral administration of 3 or 30/kg ONO-8430506 to rats. The time course of changes in plasma concentration of ONO-8430506 (A), plasma <i>ex vivo</i> LysoPLD activity (B), and plasma concentrations of various LPAs (C) are shown. Plasma LysoPLD activity is shown relative to LysoPLD activity before administration of the compound. Quantify limit of each LPA from plasma was 5 ng/ml. Results are mean ± S.D. for three rats in each group.</p