[show abstract][hide abstract] ABSTRACT: Sodium glucose cotransporters (SGLT) actively catalyse carbohydrate transport across cellular membranes. Six of the 12 known SGLT family members have the capacity to bind and/or transport monosaccharides (SGLT-1 to 6); of these, all but SGLT-5 have been characterised. Here we demonstrate that human SGLT-5 is exclusively expressed in the kidney. Four splice variants were detected and the most abundant SGLT-5-mRNA was functionally characterised. SGLT-5 mediates sodium-dependent [(14)C]-α-methyl-D-glucose (AMG) transport that can be inhibited by mannose, fructose, glucose, and galactose. Uptake studies using demonstrated high capacity transport for mannose and fructose and, to a lesser extent, glucose, AMG, and galactose. SGLT-5 mediated mannose, fructose and AMG transport was weakly (μM potency) inhibited by SGLT-2 inhibitors. In summary, we have characterised SGLT-5 as a kidney mannose transporter. Further studies are warranted to explore the physiological role of SGLT-5.
[show abstract][hide abstract] ABSTRACT: Antidiabetic effects of dipeptidyl peptidase-4 (DPP-4) inhibitors are exerted by potentiation of the biological activity of incretin hormones like glucagon-like peptide (GLP)-1. BI 1356 [proposed trade name Ondero; (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] is a novel competitive, selective, potent, and long-acting DPP-4 inhibitor under clinical development for the treatment of type 2 diabetes. The effect of 1 to 2 months of chronic dosing of BI 1356 in two different animal models was investigated. The first is a primarily genetic model (Zucker diabetic fatty rats), and the second is a nongenetic model (mice with diabetes induced by a combination of high-fat diet and low-dose streptozotocin). BI 1356 was shown to lower HbA1c after multiple dosing in both models. The improvement of glycemic control achieved in disease models of different etiology suggests that BI 1356 would also be efficacious in treating a broad spectrum of type 2 diabetic patients. In addition, multiple dosing of BI 1356 leads to a sustained increase in basal levels of active GLP-1 in the systemic circulation, with expected long-term benefits on pancreatic alpha- and beta-cells. The effects on HbA1c and GLP-1 were superior to the short-acting DPP-4 inhibitor vildagliptin, demonstrating the potential of BI 1356 as a once daily treatment for type 2 diabetes at low therapeutic doses.
Journal of Pharmacology and Experimental Therapeutics 11/2008; 328(2):556-63. · 3.89 Impact Factor
[show abstract][hide abstract] ABSTRACT: Systematic variations of the xanthine scaffold in close analogs of development compound BI 1356 led to the class of 3,5-dihydro-imidazo[4,5-d]pyridazin-4-ones which provided, after substituent screening, a series of highly potent DPP-4 inhibitors.
[show abstract][hide abstract] ABSTRACT: BI 1356 [proposed trade name ONDERO; (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] is a novel dipeptidyl peptidase (DPP)-4 inhibitor under clinical development for the treatment of type 2 diabetes. In this study, we investigated the potency, selectivity, mechanism, and duration of action of BI 1356 in vitro and in vivo and compared it with other DPP-4 inhibitors. BI 1356 inhibited DPP-4 activity in vitro with an IC(50) of approximately 1 nM, compared with sitagliptin (19 nM), alogliptin (24 nM), saxagliptin (50 nM), and vildagliptin (62 nM). BI 1356 was a competitive inhibitor, with a K(i) of 1 nM. The calculated k(off) rate for BI 1356 was 3.0 x 10(-5)/s (versus 2.1 x 10(-4)/s for vildagliptin). BI 1356 was >/=10,000-fold more selective for DPP-4 than DPP-8, DPP-9, amino-peptidases N and P, prolyloligopeptidase, trypsin, plasmin, and thrombin and was 90-fold more selective than for fibroblast activation protein in vitro. In HanWistar rats, the DPP-4 inhibition 24 h after administration of BI 1356 was more profound than with any of the other DPP-4 inhibitors. In C57BL/6J mice and Zucker fatty (fa/fa) rats, the duration of action on glucose tolerance decreased in the order BI 1356 > (sitagliptin/saxagliptin) > vildagliptin. These effects were mediated through control of glucagon-like peptide-1 and insulin. In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once-a-day DPP-4 inhibitor for the treatment of type 2 diabetes.
Journal of Pharmacology and Experimental Therapeutics 05/2008; 325(1):175-82. · 3.89 Impact Factor
[show abstract][hide abstract] ABSTRACT: A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
Journal of Medicinal Chemistry 01/2008; 50(26):6450-3. · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Novo Nordisk A/S, under license from Scios Inc, is developing NN-2211, a stable analog of the naturally occurring peptide hormone glucagon-like peptide 1 (GLP-1), which stimulates insulin release in response to increases in blood sugar levels, for the potential treatment of type 2 diabetes.
[show abstract][hide abstract] ABSTRACT: Der Entdeckung der Sulfonylharnstoffe als Antidiabetika liegt ein Zufallsbefund, nämlich die klinisch aufgetretene blutzuckersenkende Nebenwirkung von antibakteriell wirksamen Sulfonamiden, zugrunde. Systematische Weiterentwicklung der ersten Substanz, dem Carbutamid, führte zu modernen und hochpotenten Sulfonylharnstoffen der 2. Generation. Die Aufklärung des molekularen Wirkmechanismus war wichtig für die Beurteilung von potentiellen Nebenwirkungen insbesondere der kardialen Effekte der Sulfonylharnstoffe. Erst mit den nun vorliegenden Daten der großangelegten prospektiven UKPDS-Studie konnten — zumindest zum größten Teil — die Befunde der UGDP-Studie, dass mit einer Sulfonylharnstoff-Therapie ein erhöhtes kardiales Risiko verbunden ist, entkräftet werden.Zwei moderne Antidiabetika, die den molekularen Mechanismus der Sulfonylharnstoffe teilen, erweitern das Wirkprofil der Sulfonylharnstoffe. Repaglinid wie auch Nateglinid werden zu den Hauptmahlzeiten eingenommen und bewirken vornehmlich eine Reduktion der postprandialen Blutzuckerspitzen, die als unabhängiger Risikofaktor für die Entwicklung von kardiovaskulären Spätkomplikationen des Diabetes mellitus erkannt worden sind.
Pharmazie in unserer Zeit 05/2002; 31(3):252 - 262.