The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.

PreambleClassically, 1 the term synthesis has implied the construction of molecular systems as a result of the sequential formation of covalent bonds. The total syntheses of elaborate molecular compounds, such as brevetoxin B, 2 palytoxin, 3 and the calichearubicins 4 sto cite but a few examplessare triumphs for contemporary synthetic methodology. Nonetheless, the chemistry of the covalent bond has now almost been stretched to its conceptual limits. Even the best present-day synthetic chemists cannot hope to fabricate complicated nanosystemssanalogous to those witnessed in naturesusing only the currently available repertoire of covalent bond-making tools. It is time for them to look further afield for fresh challenges. 5 In order for the synthetic chemist to be able to build nanosystems, the likes of which are commonplace in the natural world, (s)he must learn to control another type of bonds specifically, the intermolecular, noncovalent bond. The chemist's drive toward the synthesis of nanoscale com-posites, employing the noncovalent bond, has led to the birth of a highly interdisciplinary field of chemical researchsviz., supramolecular chemistry 6 sin recent years. This branch of contemporary science is concerned with advancing structural complexitysbeyond the molecules from inclusion complexes toward ordered oligo-and polymolecular entities which are held together using noncovalent, intermolecular bonds. The ultimate aim of supramolecular chemistry is to become the "science of informed matter", 6a i.e., it seeks to create functioning, organized nanoscale devices 7 which will be able to stockpile and process information, by analogy with the countless marvelous examples of machine-like systems present in nature. There are two facets of modern-day chemical synthesis which are influenced by supramolecular chemistry. These are 6a (1) the creation of multicomponent supramolecular architectures utilizing noncovalent bonding interactions, i.e., supramolecular synthesis, 8 and (2) the synthesis of discrete molecular entitiessheld together using wholly covalent and mechanical 9 bondssaided and abetted by intermolecular, noncovalent interactions, i.e., supramolecular assistance to molecular synthesis. The impetus for the development of both of these aspects of synthetic supramolecular chemistry has been selfassembly, 8b,10 the spontaneous generation of well-defined supramolecular and molecular architectures from specifically "engineered" building blocks.

The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.

Two novel [2]rotaxanes, comprised of a dibenzo[24]crown-8 (DB24C8) macroring bound mechanically to a chemical “dumbbell” possessing two different recognition sitesviz., secondary dialkylammonium (NH2 +) and 4,4‘-bipyridinium (Bpym2+) unitshave been synthesized by using the supramolecular assistance to synthesis provided by, inter alia, hydrogen bonding interactions. One of these rotaxanes bears a fluorescent and redox-active anthracene (Anth) stopper unit. NMR spectroscopy and X-ray crystallography have demonstrated that the DB24C8 macroring exhibits complete selectivity for the NH2 + recognition sites, i.e., that the [2]rotaxanes exist as only one of two possible translational isomers. Deprotonation of the rotaxanes' NH2 + centers effects a quantitative displacement of the DB24C8 macroring to the Bpym2+ recognition site, an outcome that can be reversed by acid treatment. The switching processes have been investigated by 1H NMR spectroscopy and, for the Anth-bearing rotaxane, by electrochemical and photophysical measurements. Furthermore, it is possible to drive the DB24C8 macroring from the dumbbell's Bpym2+ unit, in the deprotonated form of the Anth-bearing rotaxane, by destroying the stabilizing DB24C8−Bpym2+ charge-transfer interactions via electrochemical reduction. The photochemical and photophysical properties of this rotaxane (in both its protonated and deprotonated states) have also been investigated.

A series of secondary dialkylammonium ions (RCH2)2NH2 + have been prepared, and their binding properties toward the macrocyclic polyether dibenzo[24]crown-8 (DB24C8) evaluated. By using this information, a route to a kinetically stable rotaxane-like entitystabilized by noncovalent bonding interactions between the DB24C8 macroring and the ammonium centerwas established, in which the crown ether slips over a dialkylammonium ion's stopper groups (R). However, we have found that the kinetic stability of this rotaxane-like entity is extremely dependent on the nature of the solvent in which it is dissolved, suggesting that pseudorotaxanes lie in the fuzzy domain between two sets of extremes, wherein a beadlike macrocycle and a dumbbell-like component may either (1) exist as a rotaxane or (2) be completely disassociated from one another.

GPR119 is a G protein-coupled receptor expressed predominantly in the pancreas (b-cells) and gastrointestinal tract (enteroendocrine cells) in humans. De-orphanization of GPR119 has revealed two classes of possible endogenous ligands, viz., phospholipids and fatty acid amides. Of these, oleoylethanolamide (OEA) is one of the most active ligands tested so far. This fatty acid ethanolamide is of particular interest because of its known effects of reducing food intake and body weight gain when administered to rodents. Agonists at the GPR119 receptor cause an increase in intracellular cAMP levels via G as coupling to adenylate cyclase. In vitro studies have indicated a role for GPR119 in the modulation of insulin release by pancreatic b-cells and of GLP-1 secretion by gut enteroendocrine cells. The effects of GPR119 agonists in animal models of diabetes and obesity are reviewed, and the potential value of such compounds in future therapies for these conditions is discussed.

A supramolecular system that switches reversibly, via three different states, through electrochemical adjustment of the guest properties of tetrathiafulvalene (TTF) has been developed. 1H NMR, luminescence, and absorption spectroscopies, in conjunction with LSI mass spectrometry, X-ray crystallography, and cyclic/differential pulse voltammetries, established that the π-electron-accepting (EA) tetrathiafulvalenium dication (TTF2+) binds strongly within the cavity of the π-electron-donating (ED) macrocyclic polyether 1,5-dinaphtho[38]crown-10 (1/5DN38C10), generating a host−guest complex that is stabilized by, inter alia, π−π stacking interactions. Comparable techniques have also demonstrated that neutral tetrathiafulvalene (TTF(0)) acts as an ED guest when it complexes with the EA tetracationic cyclophane cyclobis(paraquat-p-phenylene) (CBPQT4+). On the other hand, the tetrathiafulvalenium radical cation (TTF+•) is not bound by either of the hosts CBPQT4+ or 1/5DN38C10. Electrochemical experiments revealed that the three-component mixture CBPQT4+−1/5DN38C10−TTF behaves as a reversible three-pole supramolecular switch, since, depending on the potential range, TTF can be (1) free (in the TTF+• state), (2) included within the cavity of CBPQT4+ (as TTF(0)), or (3) complexed with 1/5DN38C10 (in the TTF2+ state). The system's three-pole behavior has interesting implications in relation to the design of electrochromic displays and devices capable of controlling energy- or electron-transfer processes between selected components.

On account of its pivotal role in several essential chemical and biological processes, anion binding and recognition ['] is currently arousing considerable attention within the domain of supramolecular chemistry.['] Traditionally, supramolecular chemists have positioned anion recognition sites within covalent macro(po1y)cyclic framework^^^] in a preorganizedL4] manner, so as to achieve strong anion binding. However, the discovery of self-a~sembled[~~ superniolecules that are capable of binding anions has been accomplished,[61 as supramolecular science has developed. Nevertheless, to the best of our knowledge, there has been no report to date of a self-assembled anion receptor whose components are held together entirely by hydrogen bonds. We describe here the discovery of two novel supermoleculesself-assembled utilizing only hydrogen bonds-which display either partial or complete envelopment of PF, ions in the solid state.Recently, we reportedL7] that macrocyclic polyethers form inclusion complexes, termed pseudorotaxanes,[*I of varying stoichiometries with secondary dibenzylammonium ions. In these pseudorotaxanes the ammonium ions are threaded through the macrorings and are held in place by a combination of