Glucokinase Activators for the Potential Treatment of Type 2 Diabetes

Abstract

The search for innovative and clinically-differentiated medicines for the treatment of type 2 diabetes is an active area of research for pharmaceutical companies. The discovery of allosteric Glucokinase (GK) activators in 2003 represents the first time a pharmaceutical agent was used to directly augment the actions of an enzyme by increasing its maximal velocity and substrate affinity. This discovery, coupled with translational medicine which has shown that inactivating and activating GK mutations cause glycemic diseases, has triggered an intensive medicinal chemistry effort in the field of glucokinase activators (GKAs). The antidiabetic effects of GK activators observed in animal models support the notion that these agents act to both augment insulin release from pancreatic beta-cells and suppress hepatic glucose production in the liver. This review describes the unprecedented task of optimizing small molecules in order to affect the appropriate changes in the kinetic parameters of an enzyme. In addition, a pharmacophore model for the various classes of glucokinase activators that have been described in the literature will be presented. Overall, the available data suggests that potent glucokinase activators with the desired effects on the kinetic properties of the enzyme can be designed to achieve strong and persistent antidiabetic effects. GK activators thus represent a promising new treatment for type 2 diabetes.

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

“…The search for glucokinase activators started in 1990 and has a long history (Matschinsky, 1996(Matschinsky, , 2009Grimsby et al, 2003Grimsby et al, , 2004Matschinsky et al, 2006;Pal, 2009a). A pharmacophore model of the heterogeneous chemical group of most known classes of glucokinase activators has been described previously (Grimsby et al, 2008;Sarabu et al, 2008), summarizing key structural features common to both single atomcentered (carbon or nitrogen) and aromatic ring-centered glucokinase activators, including three attachments, two of which are hydrophobic groups (with at least one consisting of an aromatic ring structure) and the other contributes a hydrogen bond donor-acceptor pair. The establishment of a crystal structure of recombinant human glucokinase was mainly put forward by FIG.…”

“…The patent literature with almost 100 compounds has been reviewed (Sarabu and Grimsby, 2005;Guertin and Grimsby, 2006;Coghlan and Leighton, 2008;Grimsby et al, 2008;Sarabu et al, 2008;Matschinsky, 2009;Pal, 2009b). The compounds can be grouped into four classes (Table 6).…”

“…It is noteworthy that some glucokinase activators act as activators at low glucose levels and as inhibitors at high glucose levels, which has recently been explained by a model (Grimsby et al, 2008). Some glucokinase activators bind to an allosteric regulatory site located 20 Å from the glucose binding site, at the interface between the large and small domains (Grimsby et al, 2003;Dunten et al, 2004;Kamata et al, 2004;Efanov et al, 2005).…”

“…Some glucokinase activators bind to an allosteric regulatory site located 20 Å from the glucose binding site, at the interface between the large and small domains (Grimsby et al, 2003;Dunten et al, 2004;Kamata et al, 2004;Efanov et al, 2005). More details with respect to the superopen conformation, glucose-bound open and closed forms have been reviewed (Grimsby et al, 2008). Dual-acting compounds are also under investigation; they activate glucokinase and inhibit glycogen phosphorylase .…”

“…Effective in rodent models (Grimsby et al, 2003(Grimsby et al, , 2008Efanov et al, 2005;Coope et al, 2006;McKerrecher et al, 2006;Fyfe et al, 2007) The second with progress to the clinic; well tolerated (Daniewski et al, 2007;Kester et al, 2009;Matschinsky, 2009;Bonadonna et al, 2010) 2007; Phase II; thereafter trials discontinued probably for priority reasons (Caulkett et al, 2005) Behaves similarly to LY2121260 (Wei et al, 2009); also prevents INS-1 cell apoptosis when induced by chronic high glucose conditions, probably via normalization of the apoptotic protein BCL2-associated agonist of cell death (BAD) and its phosphorylation (Johnson et al 2007; reviewed by Matschinsky, 2009;Wei et al, 2009;) (Futamura et al, 2006); Some of this class came down to an EC 50 of 0.076 M at 2.5 mM glucose concentration promising good in vivo results Bertram et al, 2008;Briner et al, 2007) …”