Effects of canagliflozin on SGLT1-, SGLT2-, and facilitative glucose transporter-mediated glucose transport, and on SGLT3-induced currents.

<p>CHOK cells over-expressed with human, rat, or mouse SGLT1 or SGLT2 and rat L6 myoblast cells were used. AMG or 2-DG uptake was determined and IC₅₀ values were calculated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030555#s2" target="_blank">Methods</a> section. Data of human SGLT1 and SGLT2 were presented the summary of 5 studies. Other data presented the mean value of 2 experiments. Oocytes expressed with human SGLT3 were used to determine canagliflozin effect on DNJ-induced current.</p><p>2-DG, 2-deoxy-d-glucose; AMG, alpha-methylglucoside; CHOK, Chinese hamster ovary-K; IC₅₀, concentration required to inhibit 50% of activity; SGLT, sodium glucose co-transporter; DNJ, imino sugars 1-deoxynojirimycin.</p

Effects of canagliflozin on body weight, glycemia, UGE, and respiratory exchange ratio in DIO mice and ZF rats.^a

<p>DIO mice were treated with either vehicle or canagliflozin 30 mg/kg for 4 weeks. Body weight was monitored twice per week. BG, UGE, and energy expenditure were measured at the end of this study.</p><p>BG, blood glucose; DIO, diet-induced obesity; ND, not detected; RER, respiratory exchange ratio; UGE, urinary glucose excretion; VO₂, oxygen consumption; ZF, Zucker fatty.</p>a<p>ZF rats were treated with either vehicle or canagliflozin 3 mg/kg for 3 weeks. Body weight and food intake were monitored twice per week. BG, UGE, and energy expenditure were measured at the end of this study. In addition, the weight of epididymal fat pad and liver tissue were determined during necropsy. Data are presented as mean ± SEM (<i>n</i> = 8).</p>b<p><i>p</i><0.05 compared with vehicle-treated group.</p

BG and UGE in untreated and CANA-treated ZDF rats during two GGI studies.

<p>In the first study (GGI only), a GGI was given to untreated ZDF rats (<i>n</i> = 8) to raise BG from 212±24 mg/dl to ∼475 mg/dl over 90 minutes. In the second study (Insulin+GGI), ZDF rats (<i>n</i> = 6/group) were treated with either vehicle or canagliflozin (1 mg/kg), then given insulin to lower BG to 25±1 mg/dl, and finally given the GGI to slowly raise BG. BG and UGE were measured every 5 minutes. Results shown are mean ± S.E. GGI, graded glucose infusion; BG, blood glucose; UGE, urinary glucose excretion; ZDF, Zucker diabetic fatty rats; GG1, graded glucose infusion.</p

Inhibitory effects of canagliflozin on human SGLT1 and human SGLT2.

<p>The inhibitory effect of canagliflozin on ¹⁴C-AMG uptake in CHOK-hSGLT1 and CHOK-hSGLT2 has been measured in 5 experiments. A typical inhibitory effect on CHOK-hSGLT1 (Panel A) and CHOK-hSGLT2 (Panel B) from a single experiment is presented here.</p

Effects of a 4-week treatment of canagliflozin on blood glucose and insulin levels in ZDF rats.

<p>ZDF rats were treated with different doses of canagliflozin or vehicle for 4 weeks. Fed plasma glucose levels, HbA1c, and plasma insulin were determined at the end of this study. In addition, an OGTT was conducted. Blood glucose, plasma insulin, and urine glucose excretion were measured during OGTT. Data are presented as mean ± SEM (<i>n</i> = 8).</p><p>AUC, area under the curve; HbA1c, glycated hemoglobin; OGTT, oral glucose tolerance test; ZDF, Zucker diabetic fatty.</p>a<p><i>p</i><0.05 compared with vehicle-treated group.</p

Discovery of (<i>R</i>)‑2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury

Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (<i>R</i>)-2-amino-6-borono-2-(2-(piperidin-1-yl)­ethyl)­hexanoic acid, compound <b>9</b>, inhibits human arginases I and II with IC₅₀s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure–activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound <b>9</b> and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II

Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma

This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound <b>7f</b> as a highly potent AMCase inhibitor (IC₅₀ values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150× against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound <b>7f</b> in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma

Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma

This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound <b>7f</b> as a highly potent AMCase inhibitor (IC₅₀ values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150× against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound <b>7f</b> in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma