Anne Ertan

Identification and design of a novel series of MGAT2 inhibitors

[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to naїve, p<0.01) in plasma triacylglycerol (TAG) concentration.

Clathrate design for dioxane inclusion involving singly bridged triarylmethanol hosts. Synthesis, X-ray crystal structures and thermal stabilities of five inclusion compounds

A series of singly bridged triarylmethanols, with different substituents and modified bridging units, form crystalline inclusion compounds with dioxane. X-ray diffraction studies revealed hydrogen bonds between host and guest in all these structures, and in one case also a host-to-host hydrogen bond. Most crystals contain either 1 : 1 or 2 : 1 hydrogen-bonded host–dioxane complexes, dependent on the structural parameters of the host molecule. With both host–guest and host–host hydrogen bonds present, 4 : 1, host–dioxane units are formed. Some structures accommodate additional dioxane guests which are held by van der Waals forces. The stabilities of the different dioxane clathrates were studied by thermal analysis.

Synthesis, Characterization and Unusual Reactivity of Vinylbenziodoxolones—Novel Hypervalent Iodine Reagents

A novel type of hypervalent iodine(III) reagents, vinylbenziodoxolones (VBX), has been synthesized in a one-pot reaction from 2-iodobenzoic acid. VBX is bench stable, has been thoroughly characterized and the cyclic structure is supported by X-ray analysis. The reactivity of VBX was investigated in vinylation of nitrocyclohexane, and delivered vinylated products with opposite regioselectivity compared to acyclic vinyl(aryl)iodonium salts. The reagents could become a powerful tool in vinylation reactions under both metal-free and metal-catalyzed conditions.

SYNTHESIS AND PHARMACOLOGY OF THE ENANTIOMERS OF UH301 : OPPOSING INTERACTIONS WITH 5-HT1A RECEPTORS

The (S)-enantiomer of 5-fluoro-8-hydroxy-2-(dipropylamino) tetralin [(S)-2a; (S)-UH301] was the first reported 5-HT1A receptor antagonist. We now give a full account on the synthetic effort leading to the preparation of the racemate and the enantiomers of 2a. The crystal and molecular structure of 2a. HBr has been determined by X-ray diffraction and the absolute configuration has been deduced using statistical tests of the crystallographic R values. The unit cell is tetragonal (P4(1)2(1)2) with a = b = 13.2235(2), c = 39.560(1) A and contains two crystallographically independent molecules in each asymmetric unit. The two solid state conformers differ in the conformation of the N-propyl groups. The pharmacological characterization of the enantiomers was done by use of in vivo biochemical and behavioural assays in rats. The (R)-enantiomer of 2a is a 5-HT1A receptor agonist of low potency while (S)-2a does not exhibit any agonist properties at 5-HT1A receptors. As a consequence of the opposing effects of the enantiomers, the racemate, rac-2a, does not produce any clear-cut effects in rats. The reduced efficacy of (S)-2a as compared to the well known 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino) tetralin (1;8-OH-DPAT) may be due to the fluoro-substituent induced negative potential of the aromatic ring.

AN ELECTRON PARAMAGNETIC RESONANCE INVESTIGATION OF THE REACTION OF SOME RADICAL TRAPS WITH OXOMANGANESE PORPHYRINS

The reaction of 2-methyl-N-(phenylmethylene)-2-propanamine N-oxide, 2-methyl-2-nitrosopropane and nitrosobenzene with manganese (III) porphyrins and an oxygen donor system (iodosylbenzene or sodium hypochlorite/phase-transfer catalyst) has been studied using electron paramagnetic resonance investigations. In the reaction of 2-methyl-N-(phenylmethylene)-2-propanamine N-oxide with the oxomanganese porphyrin a t-butyl radical is generated which is trapped by 2-methyl-N-(phenylmethylene)-2-propanamine N-oxide; furthermore an acylaminoxyl radical is also observed. The reaction of 2-methyl-2-nitrosopropane and nitrosobenzene with the manganese (III) porphyrins and the oxygen donor system generates the corresponding di-t-butyl- and diphenyl-aminoxyl radicals, respectively; in the case of 2-methyl-2-nitrosopropane as the substrate an acylaminoxyl radical is also detected