A novel series of 2-O-alkylascorbic acids (5a-u) was synthesized, and their scavenging activities against active oxygen species as well as their suppressive effects on the arrhythmias in rat heart ischemia-reperfusion models were evaluated. Some 2-O-alkylascorbic acids (5e-1) exhibited potent inhibiting activities against lipid peroxidation in rat brain homogenates and in alleviating effects in the ischemia-reperfusion models. Studies on the structure-activity relationship demonstrated that a free 3-enolic hydroxyl group and the longer alkyl chains substituted on the 2-hydroxyl group of ascorbic acid were beneficial for the biological and pharmacological activities. 2-O-Octadecylascorbic acid (5k, CV-3611), one of the most potent and promising compounds, markedly inhibited lipid peroxidation (IC50 = 4.3 X 10(-6) M) and alleviated myocardial lesions induced by ischemia-reperfusion at an oral dose of 1 mg/kg in rats.

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A novel series of omega-pyridylalkenoic acids has been prepared by applying the Wittig reaction. Modifications were made in the omega-aryl moiety, the alkylene chain length, the alpha-methylene group adjacent to the carbonyl group, and the carboxyl group of the molecule. The compounds were tested as inhibitors of thromboxane synthetase in an in vitro assay and in ex vivo experiments with the rat. Most members of this new class of thromboxane synthetase inhibitors (TXSI) showed good activity in both assay systems. (E)-7-Phenyl-7-(3-pyridyl)-6-heptenoic acid (9c; CV-4151) was one of the most potent compounds in in vitro enzyme inhibition (IC50 = 2.6 X 10(-8) M) and, when orally administered, the most potent and long acting in the inhibition of blood thromboxane A2 production in the rat. New conceptual models I-III for the enzyme-substrate (prostaglandin H2, PGH2) and the enzyme-TXSI interactions are proposed for understanding the molecular design and structure-activity relations.

Aim: To confirm the efficacy of vildagliptin in patients with type 2 diabetes (T2D) by testing the hypothesis that glycosylated haemoglobin (HbA1c) reduction with vildagliptin is superior to that with voglibose after 12 weeks of treatment.Methods: In this 12-week, randomized, double-blind, active-controlled, parallel-group study, the efficacy and safety of vildagliptin (50 mg bid, n = 188) was compared with that of voglibose (0.2 mg tid, n = 192) in patients with T2D who were inadequately controlled with diet and exercise.Results: The characteristics of two groups were well matched at baseline. The mean age, body mass index (BMI) and HbA1c were 59.1 years, 24.9 kg/m2 and 7.6%, respectively. At baseline, fasting plasma glucose (FPG) and 2-h postprandial glucose (PPG) were 9.01 mmol/l (162.2 mg/dl) and 13.57 mmol/l (244.3 mg/dl), respectively. The adjusted mean change in HbA1c from baseline to endpoint was −0.95 ± 0.04% in the vildagliptin-treated patients and −0.38 ± 0.04% in those receiving voglibose (between-group change = 0.57 ± 0.06%, 95% confidence interval (CI) (−0.68 to −0.46%), p < 0.001), showing that vildagliptin was superior to voglibose. Endpoint HbA1c ≤ 6.5% was achieved in 51% vildagliptin-treated patients compared with 24% patients who were on voglibose (p < 0.001). Vildagliptin also exhibited significantly (p < 0.001) greater reduction compared with voglibose in both FPG [1.34 vs. 0.43 mmol/l (24.1 vs. 7.8 mg/dl)] and 2-h PPG [2.86 vs. 1.1 mmol/l (51.5 vs. 19.8 mg/dl)]. Overall adverse events (AEs) were lower in the vildagliptin-treated patients compared with that in the voglibose-treated patients (61.2 vs. 71.4%), with no incidence of hypoglycaemia and serious adverse events with vildagliptin. Gastrointestinal AEs were significantly lower with vildagliptin compared with that of the voglibose (18.6 vs. 32.8%; p = 0.002).Conclusions: Vildagliptin (50 mg bid) showed superior efficacy and better tolerability compared with voglibose in Japanese patients with T2D.

In order to elucidate the mode of the thromboxane A2 (TXA2) receptor-ligand interaction at the molecular level, a model for the human TXA2 receptor, a member of the G protein-coupled receptor family with seven transmembrane segments, was constructed on the basis of its amino acid sequence, which was determined recently (Hirata, M.; et al. Nature 1991, 349, 617-620). First, we made a model for the human beta 2-adrenergic receptor using its amino acid sequence and the known helix arrangement of bacteriorhodopsin. Then, a TXA2 receptor model was constructed based on the beta 2 receptor model and was used to analyze the receptor-ligand interaction. The ligand-binding pocket of the TXA2 receptor includes a serine residue from segment V, an arginine residue from segment VII, and a large hydrophobic pocket between these two residues. These results are consistent with the known properties of TXA2 and TXA2 antagonists having a hydrogen-bonding group such as hydroxyl, a carboxyl group, and a hydrophobic moiety. This model should be helpful for rational design of potent TXA2 antagonists.