Glucokinase Activators | Pharmacological Data | Status |
---|---|---|
Carbon-Centered | ||
RO 0281675 (Roche)a | Lead compoundb: in vivo profile was positively characterized in rodent diabetes models (Grimsby et al., 2003, 2004); glucose reductions paralleled by an increase in insulin levels (Matschinsky, 2009) | 2000: First to be published and thoroughly clinically tested; with side effects because of its thiourea metabolite (Kester et al., 2009), the first to progress to the clinic; halted in clinical trial |
Seven derivatives of lead compound RO 0281675 | Effective in rodent models (Grimsby et al., 2003, 2004, 2008; Efanov et al., 2005; Coope et al., 2006; McKerrecher et al., 2006; Fyfe et al., 2007) | |
LY2121260 (Eli Lilly)c | Stimulation of insulin secretion and increasing glucose usage in rat hepatocytes (Efanov et al., 2005; Matschinsky, 2009); increase of both cell replication (via upregulation of insulin receptor substrate-2 and subsequent activation of protein kinase B phosphorylation) (tested in INS-1 cells) (Wei et al., 2009) | 2004; Well investigated |
PSN-GK1 (OSI) | One of the most potent (Matschinsky, 2009) | 2004; Well investigated |
PSN 010 (Prosidion/Lilly LY2599506) | Fyfe et al. (2007); Bertram et al. (2008); Briner et al. (2007); Pal (2009)b | Phase I |
Piragliatin (RO 4389620, Roche) (5, 10, or 25 mg) | 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 |
Aromatic (benzene- and pyridine)-centered | ||
Nishimura et al. (2003) | Potent | 2003; Model compound for glucokinase crystallization experiments. Structural information was interpreted according to the “mnemonic” or “slow transition” models of cooperative glucokinase kinetics (Matschinsky, 2009) |
GKA-50 (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;) | 2005; Preclinical |
Bai et al. (2007) | No biological data reported | 2007 |
Amino acid-based | ||
WO200710434 (patent number, Takeda) | No biological data known/disclosed | 2007 |
Pyrolone-based | ||
Feng et al. (2007) | No biological data known/disclosed | 2007 |
Other structures | ||
AZD1656 (AstraZeneca)b | Pyrazine derivative | Phase I (Sarabu and Grimsby, 2005); more than 20 clinical trials |
MK-0941 | Three phase II studies: the outcome was not absolutely positive | |
PSN105 | Halted in preclinical phase (Sarabu and Grimsby, 2005) | |
Class of substituted amino benzamide | (Futamura et al., 2006); Some of this class came down to an EC50 of 0.076 μM at 2.5 mM glucose concentration promising good in vivo results (Fyfe et al., 2007; Bertram et al., 2008; Briner et al., 2007) |
RO 0281675, (2R)-3-cyclopentyl-2-[4-(methanesulfonyl)phenyl]-N-(thiazol-2-yl)propionamide; LY2121260, 2-(S)-cyclohexyl-1-(R)-(4-methanesulfonylphenyl)-cyclopropanecarboxylic acid thiazol-2-ylamide; PSN-GK1, (2S)-2-[4-(cyclopropylsulfonyl)phenyl]-N-(5-fluoro-1,3-thiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide; MK-0941, (3-[[6-(ethylsulfonyl)-3-pyridinyl]oxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide; PSN105, 4,5-diphenyl-pyrimidinyl-amino substituted carbon acid.
↵a Also effective in reducing basal blood glucose levels and/or had antihyperglycemic effects in three animal models of type 2 diabetes (ob/ob mice, KKMpj-AY/J mice, Goto-Kakizaki rats). Derivatives were developed that led to new insights: chirality of the molecule is important. However, because of its potential cardiovascular risk (hERG IC50, 2.8 μM; Purkinje fiber ΔAPD90, 20%), further development of this compound was abandoned.
↵c A novel, additional role of glucokinase activators was detected: promoting β-cell growth and preventing chronic hyperglycemia-induced β-cell apoptosis.
d Promising therapeutic compound because serum lipids and insulin were reduced and there was no weight gain.