Discovery of (S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid as a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus

Abstract

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase

“…However, GKAs may cause serious side effects, as they change a sigmoidal activity curve of GK into a hyperbolic one (8,9), and consequently alter the sensing of blood glucose level by GK in pancreatic β-cells, resulting in hyperinsulinemic hypoglycemia. As an approach to avoid the side effect, moderate or hepatocyte-specific GKAs are under development (36)(37)(38). With the same rationale and based on our result, GKRP can be a target for the development of new antidiabetes drugs that activate GK in hepatocytes.…”

Addressing the Challenges of Low Clearance in Drug Research

“…Thus, medicinal chemists have become more proficient in designing metabolically stable compounds (5,6). Plus, new targets, structure classes, and dosing paradigms are being explored, such as liver targeting (7)(8)(9) and once weekly dosing (10). All these strategies need to drive the clearance very low.…”

Comparison of the Circulating Metabolite Profile of PF-04991532, a Hepatoselective Glucokinase Activator, Across Preclinical Species and Humans: Potential Implications in Metabolites in Safety Testing Assessment

“…1), with preferential GK activation in hepatocytes versus pancreatic b-cells (Pfefferkorn et al, 2012). GK is a glycolytic enzyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate (Mithieux, 1996).…”

“…In preclinical animal models of diabetes, PF-04991532 was found to robustly lower fasting and postprandial glucose and was devoid of hypoglycemic risks, leading to its selection as a clinical candidate for treating T2DM. The in vivo pharmacokinetics of PF-04991532 were characterized by high systemic plasma clearance (CL p ) values of 51 and 35 ml/min per kg in rats and dogs, respectively, and oral bioavailability of ;18% in both rats and dogs (Pfefferkorn et al, 2012). Resistance of PF-04991532 to metabolic turnover in liver microsomes and hepatocytes from a rat, dog, and human suggested that metabolic elimination would be inconsequential as a clearance mechanism in vivo.…”