GPR119 agonists mediate a unique nutrient-dependent dual elevation of both insulin and glucagon like peptide 1/glucose-dependent insulinotropic peptide levels in vivo. As a stand-alone therapy or in tandem with approved DPP-IV inhibitors, they could herald a brand new treatment paradigm for type 2 diabetes mellitus. With the passage of the first GPR119 agonist clinical candidates into Phase I trials (Arena/Ortho McNeil APD597; Metabolex MBX-2982; Prosidion/OSI PSN821) and confirmatory reports of clinical proof of concept with respect to glycemic control and incretin release, the spotlight has been set for this new class of therapeutic.

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APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P 1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P 1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.

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The reactivity of a range of pyridone and pyrazinone derivatives towards alkynes in the presence of cyclopentadienylcobaltbis(ethene) has been investigated. Depending on the nature of the substrates, [2+2+2]- or [2+2] cycloaddition, C-H, or N-H activation may occur. In the case of pyridones, the first three predominated with N-protected derivatives, whereas substrates containing N-H bonds followed an N-H activation pathway. The [2+2+2] cycloaddition of an N-butynylisoquinolone was applied successfully to the total synthesis of anhydrolycorinone. Pyrazinone substrates showed similar patterns of reactivity.

The unknown C 3v -symmetric all-cis triscyclobutenocyclohexane 1[1] is of fundamental interest as a key structure on which to probe the mechanism of [2+2+2]cycloreversions of cyclopropa-and cyclobuta-fused cyclohexanes ("tris-s-homobenzenes").[ [3] which is the result of unfavorable through-bond interactions. [2c,d] In contrast, the double bonds in 1 should not only activate by introducing further strain, [4] but also enable additional orbital symmetry control in the form of stepwise conrotatory cyclobutene ring openings, conflicting stereochemically with a concerted all-disrotatory unraveling of the cyclohexane ring. While conrotatory motion is seemingly constrained in bicyclo[n.2.0]alkenes, leading to much speculation regarding the feasibility of forbidden disroratory pathways in such systems, [5] cis-bicyclo[4.2.0]oct-7-ene, the pertinent subunit of 1 (highlighted), chooses this option. [6] More generally, such cyclohexane cycloreversions constitute one strategy for gaining access to the interior of fullerenes. [7] In addition, triene 1 (and its derivatives) are of importance structurally, because of their potential central-ring planarity, [8] and synthetically, as new precursors to novel [12]annulene isomers [9] and as new 6p-electron ligands for catalysis.[10]We report the synthesis, structure, and thermal rearrangement of the first example of structural motif 1, namely the triply annelated hydrocarbon 2 and its congeners 3 and 4, and compare their behavior to that of their common precursor, the trisbenzo analogue 5, [11] for which all-disrotatory retro-[2+2+2]cycloaddition has been proposed. [11b] To assist in the interpretation of the results, DFT calculations were employed. These calculations suggested an unexpected switch-over in the mechanism of cyclohexane ring fissure along the series.Birch reduction [12] of 5 [11b] could be controlled to give 6 a, either pure (93 %), or admixed with varying amounts (depending on the quantity of lithium used) of the mono-(6 b) and bisbenzo relatives (6 c), which were separated by column chromatography.[13] Selective dihydrogenation with Wilkinsons catalyst then furnished the targets 2-4, respectively, in good yields. Inspection of the NMR spectroscopic data of the series 2-5 reveals the trends expected for progressive, peripheral aromatization. Noticeable are the fairly invariant chemical shifts of the central cyclohexane carbon atoms, namely d = 43.3, 42.3 (average), 41.5 (average), and 40.6 ppm, respectively, and the small shielding trend, reflecting that observed for the corresponding carbon atoms in cyclobutene (d = 31.4 ppm) and benzocyclobutene (d = 29.5 ppm). Because of their novelty, X-ray structural analyses

BACKGROUND AND PURPOSEGPR119 is a Gαs-coupled 7TM receptor activated by endogenous lipids such as oleoylethanolamide (OEA) and by the dietary triglyceride metabolite 2-monoacylglycerol. GPR119 stimulates enteroendocrine hormone and insulin secretion. But despite massive drug discovery efforts in the field, very little is known about the basic molecular pharmacology of GPR119. EXPERIMENTAL APPROACHGPR119 receptor signalling was studied in transfected cells. Mutational mapping (30 mutations in 23 positions) was performed on residues required for ligand-independent and agonist-induced GPR119 activation (AR231453 and OEA). Novel Rosetta-based receptor modelling was applied, using a composite template approach with segments from different X-ray structures and fully flexible ligand docking. KEY RESULTSThe increased signalling induced by increasing the cell surface expression of GPR119 in the absence of agonist and the inhibitory effect of two synthetic inverse agonists demonstrated that GRP119 signals with a high degree of constitutive activity through the Gαs pathway. The mutational maps for AR231453 and OEA were very similar and, surprisingly, also similar to the mutational map for residues affecting the constitutive signalling -albeit with key differences. Surprisingly, almost all residues in extracellular loop-2b were important for the constitutive activity. The molecular modelling and docking demonstrated that AR231453 binds in a 'vertical' pocket in between mutational hits reaching from the centre of the receptor out to extracellular loop-2b. CONCLUSIONS AND IMPLICATIONSThe high constitutive activity of GPR119 should be taken into account in future drug discovery efforts, which can now be guided by the detailed knowledge of the physiochemical properties of the extended ligand-binding pocket. Abbreviations7TM, seven transmembrane; ECL, extracellular loop; OEA, oleoylethanolamide; REU, Rosetta energy units; RMSD, root mean square deviation.