In addition researchers studying GPR agonists favor the deve
In addition, researchers studying GPR119 agonists favor the developing of candidate drugs that are more potent than DPP-4 inhibitors given that the latter are moderate agents in the treatment of DM. Although it parecoxib is unclear why Sanofi-Aventis chose to terminate collaboration with Metabolex (now Cymabay Therapeutics) on MBX-2982 (Metabolex reported that there were no major safety or efficacy concerns), I assume that it was mainly because of its low efficacy compared with sitagliptin. Thus, a way to rekindle the enthusiasm for GPR119 agonist development would be to upload the details of potent candidates currently in clinical trials. To achieve this goal, researchers would need to try a variety of different scaffolds, and virtual screening and/or combinatorial chemistry might be helpful to this end .
WT strategy In this defensive strategy, there is a need to set up an alternative plan to the development of GPR119 agonists. Through careful weighing up of the pros and cons of promising investigational drugs (Table 2), back up programs can be selected. In particular, it is necessary to pay attention to the cardiovascular risk of candidate compounds in conjunction with their own specific adverse effects. The candidate with multiple adverse effects does not always make it a second or third priority compound, making risk–benefit analyses more difficult. For example, sodium–glucose-linked transporter (SGLT) inhibitors resulted in adverse events, such as constipation, diarrhea, nausea, urinary frequency and genitourinary infections during phase II and III trials . However, dapagliflozin was recently marketed in Europe and the FDA approved canagliflozin in March 2013, making it the first SGLT2 inhibitor to be approved in the USA (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm). Given the current status of the pharmaceutical industry, enriching the clinical pipeline or program diversification might not be easy for small biotech companies that struggle with budget and performance. Therefore, a back-up plan, together with strategy setting differentiated from large pharmaceutical companies, might be needed . Researchers developing GPR119 agonists will need to keep an eye on recent findings about GPR119 under a risk-mitigated balanced back-up research portfolio. At the same time, quick feedback on the synthesis and biological evaluation of candidates expediting different chemotype trials might be useful. In the case of a worst-case scenario regarding GPR119 agonist R&D, swift change to a ‘plan B’ might be necessary.
Concluding remarks In this review, I discussed the pros and cons of GPR119 agonists as potential antidiabetes agents through a SWOT analysis (Fig. 1). On the basis of this analysis, GPR119 is unlikely to regain its previous popularity because there are significant weaknesses and threats relating to this drug target. Under current R&D circumstances, I suggest that GPR119 researchers could use this SWOT analysis to complete analyses of their own candidates for the eventual success of their antidiabetes research projects. Numerous researchers from the pharmaceutical industry and academia have been involved in this drug target and it is probable that conclusive evaluations or scientific findings will appear as research results continue to accumulate.
The need to address the worldwide pandemic of Type 2 diabetes (T2D) can hardly be overstated. The current treatments for this chronic disorder either fail to be effective over time or present limiting safety risks, emphasizing a strong medical need for novel approaches., The G-protein-coupled receptor GPR119, predominantly expressed in pancreatic β-cells and enteroendocrine L-cells in the gut, has recently emerged as a promising drug target for T2D due to its role in regulating glucose homeostasis via modulation of incretin and insulin secretion., , , Since the ground-breaking publications disclosing GPR119 agonists such as and by Arena and Prosidion research groups respectively,, over 100 patent applications have been filed that generally revolve around a common pharmacophore shown in ., To date, several organizations have progressed GPR119 agonists into the clinic. Previously disclosed compounds and are depicted in , and structurally also fall under the common GPR119 pharmacophore. Our own efforts towards identifying novel agonists of GPR119 that display this ‘classical’ pharmacophore will be disclosed elsewhere. In addition to these efforts, we undertook a high-throughput screening (HTS) campaign on a ∼2million compound collection, searching for new chemical matter that did not share structural similarity with known agonists.