Taspoglutide, a novel human once-weekly analogue of glucagon-like peptide-1, improves glucose homeostasis and body weight in the Zucker diabetic fatty rat

Aim: Glucagon-like peptide-1 (GLP-1) receptor agonists are a novel class of pharmacotherapy for type 2 diabetes. We investigated the effects of a novel, long-acting human GLP-1 analogue, taspoglutide, in the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. Methods: Blood glucose and plasma levels of insulin, peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP) and triglycerides were measured during oral glucose tolerance tests (oGTT) conducted in ZDF rats treated acutely or chronically with a single long-acting dose of taspoglutide. Pioglitazone was used as a positive control in the chronic study. Postprandial glucose, body weight, glycaemic control and insulin sensitivity were assessed over 21 days in chronically treated animals. Results: Acute treatment with taspoglutide reduced glucose excursion and increased insulin response during oGTT. In chronically treated rats, glucose excursion and levels of GIP, PYY and triglycerides during oGTT on day 21 were significantly reduced. Postprandial glucose levels were significantly lower than vehicle controls by day 15. A significant reduction in body weight gain was noticed by day 8, and continued until the end of the study when body weight was approximately 7% lower in rats treated with taspoglutide compared to vehicle. Glycaemic control (increased levels of 1,5-anhydroglucitol) and insulin sensitivity (Matsuda index) were improved by taspoglutide treatment. Conclusions: Taspoglutide showed typical effects of native GLP-1, with improvement in glucose tolerance, postprandial glucose, body weight, glycaemic control and insulin sensitivity

cGMP-stimulated cyclic nucleotide phosphodiesterase regulates the basal calcium current in human atrial myocytes.

EHNA (Erythro-9-[2-hydroxy-3-nonyl]adenine) is a wellknown inhibitor of adenosine deaminase. Recently, EHNA was shown to block the activity of purified soluble cGMPstimulated phosphodiesterase (PDE2) from frog, human, and porcine heart with an apparent Ki value of approximately 1 microM and with negligible effects on Ca2+/calmodulin PDE (PDE1), cGMP-inhibited PDE (PDE3), and low Km cAMP-specific PDE (PDE4) (Méry, P.F., C. Pavoine, F. Pecker, and R. Fischmeister. 1995. Mol. Pharmacol. 48:121-130; Podzuweit, T., P. Nennstiel, and A. Muller. 1995. Cell. Signalling. 7:733- 738). To investigate the role of PDE2 in the regulation of cardiac L-type Ca2+ current (ICa), we have examined the effect of EHNA on ICa in freshly isolated human atrial myocytes. Extracellular application of 0.1-10 microM EHNA induced an increase in the amplitude of basal ICa ( approximately 80% at 1 microM) without modification of the current-voltage or inactivation curves. The maximal stimulatory effect of EHNA on ICa was comparable in amplitude with the maximal effect of isoprenaline (1 microM), and the two effects were not additive. The effect of EHNA was not a result of adenosine deaminase inhibition, since 2'-deoxycoformycin (1-30 microM), another adenosine deaminase inhibitor with no effect on PDE2, or adenosine (1-10 microM) did not increase ICa. In the absence of intracellular GTP, the substrate of guanylyl cyclase, EHNA did not increase ICa. However, under similar conditions, intracellular perfusion with 0.5 microM cGMP produced an 80% increase in ICa. As opposed to human cardiomyocytes, EHNA (1-10 microM) did not modify ICa in isolated rat ventricular and atrial myocytes. We conclude that basal ICa is controlled by PDE2 activity in human atrial myocytes. Both PDE2 and PDE3 may contribute to keep the cyclic nucleotides concentrations at minimum in the absence of adenylyl and/or guanylyl cyclase stimulation

Taspoglutide, a novel human once-weekly GLP-1 analogue, protects pancreatic β-cells in vitro and preserves islet structure and function in the Zucker diabetic fatty rat in vivo

Glucagon-like peptide-1 (GLP-1) has protective effects on pancreatic β-cells. We evaluated the effects of a novel, long-acting human GLP-1 analogue, taspoglutide, on β-cells in vitro and in vivo

Dalcetrapib:no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats

BACKGROUND AND PURPOSE: The association between torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model. EXPERIMENTAL APPROACH: Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving torcetrapib 10, 40 or 80 mg·kg(−1)·day(−1); dalcetrapib 100, 300 or 500 mg(−1)·kg·day(−1); or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days' treatment with torcetrapib 40 mg·kg(−1)·day(−1), dalcetrapib 500 mg·kg(−1)·day(−1) or vehicle was measured by quantitative polymerase chain reaction. KEY RESULTS: Torcetrapib transiently increased mean AP in normotensive rats (+3.7 ± 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 ± 0.6 mmHg with 40 mg·kg(−1)·day(−1) at day 1 (P < 0.05 versus placebo)], which lasted over the treatment period. No changes in AP or heart rate were observed with dalcetrapib. Torcetrapib, but not dalcetrapib, increased RAAS-related mRNAs in adrenal glands and aortas. CONCLUSIONS AND IMPLICATIONS: In contrast to torcetrapib, dalcetrapib did not increase blood pressure or RAAS-related gene expression in rats, suggesting that the off-target effects of torcetrapib are not a common feature of all compounds acting on cholesteryl ester transfer protein

5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures

Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease and cancer. There is increasing evidence suggesting an important role for the 5-HT2C receptor in appetite control. Collaboration between F. Hoffmann-La Roche Ltd and Vernalis Research Ltd has allowed rapid construction of a solid structure–activity relationship around a pyrroloindole core. A one-pot Sonogashira reaction followed by nucleophilic double cyclisation allows an elegant and expedient route to this central motif. Introduction of a (2S)-aminopropyl group in place of the aminoethyl endogenous ligand side-chain enhanced the affinity at the 5-HT2C receptor and reduced affinity towards monoamine oxidase enzymes (MAO). Sulfamidate reagents were found to be very effective for the introduction of the 2-aminopropyl moiety in a stereoselective manner. The substitution at position 5 (indole numbering) was found to be crucial for both affinity and selectivity. Pyrroloindoles bearing an alkoxyether in this position exhibit promising pharmacokinetic parameters in rodent and significant reduction of food intake, after per os application