In order to investigate whether this off target

In order to investigate whether this off-target activity was related to a particular structural feature of this Semaxanib or was characteristic of the series, compounds , and were selected as being matched pairs with compound but with structural variation in terms of the R, R and R groups, respectively. Based on the DMPK profiles of these compounds in mouse, we selected doses that would give coverage of the murine EC for the entire duration of the experiment. Upon testing these compounds in vivo, and confirming that the targeted exposures had been achieved, we again observed glucose lowering in both wild-type and knock-out animals in all three cases. This led us to conclude that the pharmacophore displayed by this chemical series was giving glucose lowering effects through mechanisms other than GPR119 (). In efforts to identify what target may be responsible for these effects, compound was screened against a panel of 100 targets. Only three targets were identified (5HT2A, D4.2 & CCR5) that gave >75% activity at a concentration of 30μM. In contrast, compound was inactive against both D4.2 & CCR5 (<10% activity at 30μM) yet still showed off-target activity. Compounds from other series being profiled in the project which showed glucose lowering in the wild type but not the knock-out mouse, had similar levels of activity against 5HT2A (data not shown) suggesting that this was not the target responsible. Further attempts to ascertain the cause of the ‘off-target’ effects have not provided a clear outcome at present. In summary, optimisation of a novel series of GPR119 agonists allowed us to identify compounds that were potent against the receptor with reduced hERG liabilities relative to the initial lead as exemplified by compound . A representative example had excellent pharmacokinetic properties and displayed excellent glucose lowering in vivo. However the glucose lowering effects were also observed in a GPR119 knock-out mouse model leading us to conclude that the biological effects were not exclusively due to GPR119 agonism. Further studies on alternative chemical series that do not exhibit activity in the GPR119 knock-out mouse model will be reported in due course Acknowledgement
G-protein-coupled receptor 119 (GPR119) is a recently deorphanized GPCR that belongs to the class A (rhodopsin-like) family (reviewed in , , ). The tissue distribution of this receptor is unique in that it has a highly expressed pattern in pancreatic islets and in some regions of the gastrointestinal (GI) tract in humans , , . Based upon this distribution profile and the suggestion that GPR119 is related to glucose homeostasis, research was initiated for its development as an antidiabetes agent. The activation of GPR119 can occur through endogenous ligands containing oleic acid, such as oleoylethanolamide (OEA) or synthetic small molecules , . It is generally thought that GPR119 agonists cause an increase in intracellular cAMP levels via Gαs coupling, which leads to an increase in adenylate cyclase activity. In addition, this increase in cAMP is also observed in cells stably transfected with cDNA encoding GPR119, whereas untransfected cells do not respond to GPR119 agonists , . As mentioned in previous reviews , , , the activation of GPR119 leads to glucose-dependent insulin secretion in pancreatic β cells, along with glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) release in intestinal K cells and L cells, respectively. Based upon these findings, many pharmaceutical companies have focused on this receptor and its potential as a target for new antidiabetes drugs. For example, Semple . claim that they discovered the first potent and orally efficacious agonist of GPR119, in the form of AR231453 . Following this initial enthusiasm, numerous GPR119 agonists with diverse chemotypes have been patented, some which are highlighted in . Although novel GPR119 agonists are introduced continually in published articles , , , GPR119 is not receiving as much interest as in previous years, owing to various obstacles to its agonist development. In this review, I discuss this phenomenon through the use of a strengths, weaknesses, opportunities, and threats (SWOT) analysis of GPR119 and highlight strategies that could be used to overcome these obstacles in GPR119 agonist development.