Su Youn Nam

Discovery of 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methylpyridin-2-yl)-benzamide as a novel glucokinase activator (GKA) for the treatment of type 2 diabetes mellitus.

Novel heteroaryl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucose uptake and glucokinase activity stimulated by 10mM glucose in rat hepatocytes. From a library of synthesized compounds, 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methyl pyridin-2-yl)-benzamide (19e) was identified as a potent glucokinase activator with assays demonstrating an EC50 of 315nM and the induction of a 2.23 fold increase in glucose uptake. Compound 19e exhibited a glucose AUC reduction of 32% (50mg/kg) in an OGTT study with C57BL/6J mice compared to 28% for metformin (300mg/kg). Single treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity, while in a two-week repeated dose study with ob/ob mice, the compound significantly decreased blood glucose levels with no evidence of hypoglycemia risk. In addition, 19e exhibited favorable pharmacokinetic parameters in mice and rats and excellent safety margins in liver and testicular toxicity studies. Compound 19e was therefore selected as a development candidate for the potential treatment of type 2 diabetes.

Tu1827 Yh4808, a Potent, Highly Selective K+-Competitive Acid Blocker, Suppressed Rat Acute Reflux Esophagitis More Effectively Than Esomeprazole

Introduction: Proton pump inhibitors (PPIs) are now widely used for the treatment of acidrelated diseases, such as peptic ulcer and gastroesophageal reflux disease (GERD). PPIs which are weak-base prodrugs are activated in an acidic condition and only inhibit H+/K+ATPase that has already been activated. Therefore, the effect of PPIs on acid-related diseases is slow onset and their maximum efficacy can be achieved after several days of dosing, leading to unmet medical needs such as nocturnal acid breakthrough and unsatisfied symptom relief. Methods: We investigated the pharmacological profiles of YH4808, a novel potent, highly selective K+-competitive acid blocker (P-CAB), in terms of hog gastric H+/K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in animal models, in comparison with esomeprazole. In addition, a quantitative whole body autoradiography (QWBA) study was performed with [14C]YH4808 (10 mg/kg) in rats to characterize tissue distribution. Results: YH4808 inhibited H+/K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 3.4 nM which is more potent than that of esomeprazole. The inhibitory mechanism of YH4808 on H+/K+-ATPase was a competitive antagonism to the K+-binding site of H+/K+-ATPase, and it was also a reversible inhibition. In a selectivity assay, YH4808 showed 3,000-fold greater selectivity against Na+/K+-ATPase. In pylorus-ligated rats, oral administration of YH4808 inhibited basal acid secretion in a dose-dependent manner with the ID50 value of 1.1 mg/kg. Anti-secretory activity of YH4808 against histamine-stimulated acid secretion in rats after IV injection (ID50=0.1 mg/kg) was stronger than that of esomeprazole (ID50=0.9 mg/kg). In Heidenhain pouch dogs, IV administration of YH4808 inhibited histamine-stimulated acid secretion in a dose-dependent manner with almost complete inhibition at the dose of 0.6 mg/kg. In a reflux esophagitis model, intraduodenal administration of YH4808 prevented esophageal lesions by 30, 82 and 91% at a dose of 1, 3, and 10 mg/kg, respectively while esomeprazole reduced the lesion by 47% at 10 mg/kg. A QWBA study in rats showed YH4808 accumulated and was retained in the gastric tissue for more than 24h after oral administration. Conclusion: YH4808, a novel selective P-CAB exerted a potent, longer-lasting anti-secretory efficacy through high accumulation in the gastric tissue, which translated into the more effective inhibition of reflux esophagitis than esomeprazole. These findings indicate that YH4808 can provide significant clinical benefits to patients with acid-related diseases.