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  • It appears that not all


    It appears that not all GPR119 agonists require a high dose to elicit acceptable Taxifolin synthesis control. According to preclinical data presented at the GTCbio Diabetes Summit, a 3mg/kg dose of AR-7947 was enough to induce similar blood glucose-lowering effects compared to those achieved by 30mg/kg sitagliptin in an oral glucose tolerance test (OGTT) using female ZDF rats. If this result translates to a clinical trial, the doses would be lower than those of MBX-2982 or PSN-821. In addition, given that GPR119 agonists stimulate the release of GLP-1, the benefits of GLP-1 can be expected as described in the work of Meier [17] along with body weight-lowering effects mentioned in the Strengths section above. Therefore, the ability of GPR119 agonists to induce the release of GLP-1 is important and, thus, they could also be viewed as indirect small-molecule GLP-1 receptor agonists.
    ST strategy To maximize the beneficial effects of GLP-1 induced by GPR119 agonists, DPP-4 inhibitors are needed because the native GLP-1 peptide has low stability in vivo, with a half-life of approximately 2min. DPP-4 inhibitors achieve glycemic control through the inhibition of GLP-1 breakdown by DPP-4. Thus, GPR119 agonists are expected to show additive or synergistic effects when administered with DPP-4 inhibitors, as reported for some GPR119 agonists 30, 31, 32. Although long-term adverse effects of DPP-4 inhibitors are inconclusive, their combination with GPR119 agonists is likely to reduce the dose of DPP-4 inhibitors required, given that the absolute amount of GLP-1 in plasma will increase owing to the agonistic action of GPR119 along with insulin secretion caused by GPR119 agonists. Similarly, Barba et al. attempted to synthesize compounds with dual actions, as seen for the combination of GPR119 agonists and DPP-4 inhibitors, as an all-in-one strategy [33]. Utilizing fragment-based drug discovery tactics, the cyanopyrrolidine pharmacophore of known DPP-4 inhibitors (e.g. vildagliptin and saxagliptin) was introduced onto the aryl moiety of their GPR119 agonists (Table 1). Such drugs will be beneficial in terms of patient compliance in addition to strong intellectual property (IP) results for these researchers, if they are able to provide potent candidates having both properties in one molecule. Most pharmaceutical companies developing GPR119 agonists pursue single therapies first, relying on the activities coming solely from GPR119 agonists. However, if it proves difficult to draw intrinsic activity out of GPR19 agonists, or if the candidates are not potent enough, a quick strategy change to the development of combination therapy might be necessary. In addition, given that GPR119 activation leads to an increase in GIP as well as GLP-1, Chu et al. published a patent relating to the treatment of osteoporosis using GPR119 agonists [34]. In multiple studies, GIP has been shown to promote bone formation and this can be used to probe GPR119 agonists as agents for treating conditions characterized by low bone mass [35]. Although this has yet to be clinically proven, the patent is valuable from a drug-repositioning perspective. In addition, in a clinical study of GSK1292263 in patients who were dyslipidemic but who did not have diabetes, when dosed alone or with atorvastatin, the compound gave promising results. This is another example of an attempt to reprofile GSK1292263 as an antidyslipidemia agent even if it failed as an antidiabetes drug.
    WO strategy Although GSK1292263 had a loss of efficacy during clinical trial, it retained its efficacy in OGTTs after eight weeks of dosing and decreased HbA1c after seven weeks in ZDF rats [18]. Interestingly, in rodent models (rats and mice), it did not inhibit gastric emptying and had no effect on body weight, whereas PSN-821 inhibited gastric emptying in lean male SD rats and lowered body weight in DIO female Wistar rats [18]. Although the structure of PSN-821 has not been disclosed and the animal model used was different, the structural dissimilarities between these compounds might have played a crucial role in producing these different clinical results. A detailed comparison study using representative GPR119 agonists under standardized biological conditions will provide clues on the loss of efficacy or tachyphylaxis events of either compound.