Shuhei Miyazawa

E3710, a new proton pump inhibitor, with a long lasting inhibitory effect on gastric acid secretion

We have investigated the pharmacology of sodium (R)-2-[4-(2,2-dimethyl-1,3-dioxan-5-yl) methoxy-3,5-dimethylpyridin-2-yl]methylsulfinyl-1H-benzimidazol (E3710), a new proton pump inhibitor (PPI), and its effect on gastric acid secretion. E3710 irreversibly inhibited H+,K+-ATPase activity in pig gastric vesicles with an acidic internal environment with an IC50 of 0.28 μM. Administration of E3710 (0.1, 0.2, 0.4, and 0.8 mg/kg; n = 6) intraduodenally in a gastric fistula model in dogs inhibited histamine-stimulated gastric acid secretion at 0 to 2 and 24 to 26 h after administration with ED50 values of 0.18 and 0.22 mg/kg, respectively. The inhibition by E3710 was 2.3 times more potent than that of another representative PPI, esomeprazole (0.2, 0.4, 0.8, and 1.6 mg/kg; n = 6) at 0 to 2 h after administration (ED50 = 0.40 mg/kg) and 2.8 times more potent at 24 to 26 h (ED50 = 0.71 mg/kg). In the gastric fistula dogs, the intragastric pH was ≥4 for 17% (n = 27) of a 24-h period with vehicle alone, but when E3710 was administered, at 0.2 (n = 4), 0.4 (n = 8), and 0.8 mg/kg (n = 5), the pH was ≥4 for 40, 79, and 88% of a day, respectively. The corresponding values for esomeprazole at 0.8 (n = 4) and 1.6 mg/kg (n = 8) were 55 and 59%, respectively. In a crossover study with vehicle, E3710 at 0.4 mg/kg and esomeprazole at 1.6 mg/kg (n = 6), E3710 increased the intragastric pH to >4 for 82% of a day compared with 61% of a day with esomeprazole. These results show that E3710 is a long-acting inhibitor of gastric acid secretion and a promising novel therapy for acid-related diseases, such as gastroesophageal reflux disease.

Synthesis of (S)-N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyloxy) [carbonyl-14C]benzamide monohydrochloride (14C-E3620)

(S)-N-(endo-8-Methyl-8-azabicyclo[3.2.1]oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyloxy)[carbonyl-14C]benzamide monohydrochloride (14C-E3620, 1 1), which was required for a study of the pharmacokinetic profile of E3620, is not only a potent antagonist of 5-HT3 receptors but also a potent agonist of 5-HT4 receptors. It was synthesized using (S)-5-chloro-4-(2,5-dimethylpyrrol-1-yl)-2-(1-methyl-2-butynyloxy)[carboxy-14C]benzoic acid (8) as the labelled starting material.