David Edward Tupper

The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053)

Abstract 4′-N-desmethyl olanzapine (2), olanzapine 4′-N-oxide (3) and 2-hydroxymethyl olanzapine (5), have been prepared and their pharmacology compared to that of the parent compound olanzapine (1). The 4′-N-quaternary glucuronide (8) has also been prepared.

Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a Potent, Selective Metabotropic Glutamate Receptor Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino Terminal Domain Structures.

As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.

Bicyclo[2.2-1]heptanes as novel triple re-uptake inhibitors for the treatment of depression

A series of substituted naphthyl containing chiral [2.2.1] bicycloheptanes were prepared utilizing asymmetric Diels-Alder chemistry. This paper describes structure-activity relationships in this series. The N-methyl 2-naphthyl analogue (16d) and its des-methyl analogue (17d) are active triple re-uptake inhibitors both in vivo and in vitro.

Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.

Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.

First alkylation of a 1-methoxy-substituted tricarbonyl(η5-cyclohexadienyl)iron(1 +) complex

Abstract A 1,2-dimethoxy-substituted tricarbonyl(η 5 -cyclohexadienyl(iron(1 +) cation was alkylated predominantly at C(1) to afford an adduct which was converted into a 1-carbomethoxymethyl-2-methoxy-substituted dienyl complex in the first regiocontrolled reaction sequence involving a 1-methoxydienyl complex as a synthetic intermediate.

Lanthanide Shift Reagents. Paper 21. Interaction of Arenes with Silver/Lanthanide Shift Reagent and Comparison with Chromium Tricarbonyl Complexes

Abstract Lanthanide shift reagents can bring about dramatic simplifications of highly complex NMR spectra1,2. The applicability of the commonest of these (the thd and fod chelates of Eu, Pr and Yb) has been restricted to those molecules possessing a suitable N, O or S donor atom, although they may turn up in unusual guises, e.g. in quaternary ammonium compounds3.

Heteroarene-fused benzodiazepines. Part 1. Synthesis of thieno-[2,3-b][1,5]-, -[3,2-b][1,5]-, and -[3,4-b][1,5]-benzodiazepinones

The synthesis of the 4H-thieno-[2,3-b][1,5]-, -[3,2-b][1,5]-, and -[3,4-b][1,5]-benzodiazepinone ring systems is described. Sodium methylsulphinylmethanide was used for the intramolecular cyclisation of the intermediate amino-esters (5), (9), and (14). However, attempted cyclisation of ethyl 2-(2-amino-4-fluoroanilino)-5-ethyl-thiophen-3-carboxylate (5b) with sodium hydride at a higher temperature caused rearrangement to a benzimidazolone (12).

s-Triazines. Part V. Synthesis and hydrolytic stability of 2,4-dihalogeno-6-heteroaryl-s-triazines

The first and second hydrolysis rate coefficients for the title compounds are discussed in terms of variation of the heteroaryl substituent (substituted phenyl, furyl, pyrrolyl, or thienyl) and of the halogen substituents (X = F, Cl, I, or CCl3). Electron-withdrawing substituents in the aryl rings enhance the rate coefficients, which are linearly related to the pKa values of the analogous dioxo-products (III) for phenyl, thienyl, or pyrrolyl substituents. Evidence is presented to show that the rate-determining step in the hydrolysis is nucleophilic attack on the triazine rather than carbon–halogen bond rupture.

Synthesis of novel 8- and 10-substituted clavine derivatives

The hydrogen at C-10 of agroclavine was readily removed by butyl-lithium to give an ambident carbanion. The addition of a range of electrophiles produced 10-substituted agroclavines (2a–l), 8-substituted lysergines (3e–i), and isolysergic acid derivatives (3c, d). Catalytic reduction of 1-methyl-10-propylagroclavine (2c) yielded 1-methyl-10-propylpyroclavine (5b) as the major product. Oxidation of 8-methylthiolysergine (3g) followed by an elimination reaction produced the alkaloid lysergene (7).

Chemistry of adamantane. Part IX. 1,2-Difunctional adamantanes; synthesis and reactions of protoadamantane-4-spiro-oxiran

The synthesis of protoadamantane-4-spiro-oxiran {octahydrospiro[2,5-methano-1H-indene-7,2′-oxiran]} and its isomerisation to protoadamantane-4-carbaldehyde are described. Electrophilic cleavage of the oxiran ring with simultaneous rearrangement gives 1,2-difunctional adamantane derivatives. Reactions of lithium carbenoids, from benzylidyne chloride and benzylidene bromide, with protoadamantan-4-one mainly lead to protoadamantan-4-yl phenyl ketone. 4-Phenylprotoadamantan-4-ols on treatment with acid preferentially undergo elimination to give 4-phenylprotoadamantene.