C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators.

Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.

Discovery of 2-pyridylureas as glucokinase activators.

Glucokinase (GK) is the rate-limiting step for insulin release from the pancreas in response to high levels of glucose. Flux through GK also contributes to reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate GK may address this issue. Herein we report the identification and initial optimization of a novel series of glucokinase activators (GKAs). Optimization led to the identification of 33 as a compound that displayed activity in an oral glucose tolerance test (OGTT) in normal and diabetic mice.

Characterization of a novel glucokinase activator in rat and mouse models.

Glucokinase (GK) is a hexokinase isozyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. Glucokinase activators are being investigated as potential diabetes therapies because of their effects on hepatic glucose output and/or insulin secretion. Here, we have examined the efficacy and mechanisms of action of a novel glucokinase activator, GKA23. In vitro, GKA23 increased the affinity of rat and mouse glucokinase for glucose, and increased glucose uptake in primary rat hepatocytes. In vivo, GKA23 treatment improved glucose homeostasis in rats by enhancing beta cell insulin secretion and suppressing hepatic glucose production. Sub-chronic GKA23 treatment of mice fed a high-fat diet resulted in improved glucose homeostasis and lipid profile.

Toxicity from modafinil ingestion.

INTRODUCTION: Modafanil, a non-amphetamine stimulant, is used for narcolepsy, sleep apnea, and shift work sleep disorder. There is little available information on the toxicity of modafinil overdose. METHOD: We performed a retrospective multi-poison center chart review of patients from 11 states who had a single substance ingestion of modafanil with follow up to a known outcome for the years 2000-2007. Data collected included age, gender, dose ingested, clinical effects, length of hospital stay, and medical outcome. RESULTS: There were 137 patients, of whom 85 (63%) were female. Ages ranged from 1 to 82 years with a mean and median of 22 years (+18) and 20 years, respectively, with 43 patients (31%) aged <6 years. Most frequently reported clinical effects were tachycardia (n = 38), insomnia (n = 33), agitation (n = 27), dizziness (n = 25), and anxiety (n = 24). Forty-five patients were managed at home and 92 in a health-care setting, with only 23 (17%) requiring a medical admission. Therapies included benzodiazepines (n = 14), diphenhydramine (n = 5), beta-blockers (n = 3), haloperidol (n = 2), IV fluid hydration (n = 2), and one each of nitroglycerin, epinephrine, benztropine, and promethazine. CONCLUSIONS: In this case series, clinical effects of modafinil overdoses were generally mild with predominantly tachycardia and CNS toxicity. However, clinically significant effects warranting specific therapy occurred in a minority of patients.