A potent, selective, orally active LXR agonist was identified from focused libraries of tertiary amines. GW3965 (12) recruits the steroid receptor coactivator 1 to human LXRα in a cell-free ...ligand-sensing assay with an EC50 of 125 nM and profiles as a full agonist on hLXRα and hLXRβ in cell-based reporter gene assays with EC50's of 190 and 30 nM, respectively. After oral dosing at 10 mg/kg to C57BL/6 mice, 12 increased expression of the reverse cholesterol transporter ABCA1 in the small intestine and peripheral macrophages and increased the plasma concentrations of HDL cholesterol by 30%. 12 will be a valuable chemical tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metabolism.
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Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment ...of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo3.1.0hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.
A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, ...(1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.
Oxidation of 4-(3-methoxy-4-hydroxymethylphenoxy)methyl polystyrene resin produced AMEBA resin
1, a novel acid sensitive aldehyde resin. Reductive amination of AMEBA resin generated resin bound ...amines which were derivatized as sulfonamides, amides, ureas, and carbamates. Cleavage of the resin under mild acidic conditions generated the derivatized amines in high purity and moderate yield.
AMEBA resin
1 is used for traceless solid phase synthesis of secondary sulfonamides, amides, ureas, and carbamates from primary amines.
We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor δ (PPARδ). Several hits were identified from our ...original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to
7k (GW501516) and
7l (GW0742), which shows an EC
50 of 1.1 nM against PPARδ with 1000-fold selectivity over the other human subtypes.
We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor δ (PPARδ). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to
7k (GW501516) and
7l (GW0742), which shows an EC
50 of 1.1 nM against PPARδ with 1000 fold selectivity over the other human subtypes.
The demonstrated functional interaction of metabotropic glutamate 5 (mGlu5) receptors with N-methyl-d-aspartate (NMDA) receptors has prompted speculation that their activation may offer a potential ...treatment for aspects of schizophrenia. Development of selective mGlu5 agonists has been difficult, but several different positive allosteric modulator (PAM) molecules have now been identified. This study describes two novel mGlu5 PAMs, LSN2463359 (N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide) and LSN2814617 (7S)-3-tert-butyl-7-3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl-5,6,7,8-tetrahydro1,2,4triazolo4,3-Apyridine, which are useful tools for this field of research. Both compounds are potent and selective potentiators of human and rat mGlu5 receptors in vitro, displaying curve shift ratios of two to three fold in the concentration–response relationship to glutamate or the glutamate receptor agonist, DHPG, with no detectable intrinsic agonist properties. Both compounds displaced the mGlu5 receptor antagonist radioligand, 3HMPEP in vitro and, following oral administration reached brain concentrations sufficient to occupy hippocampal mGlu5 receptors as measured in vivo by dose-dependent displacement from the hippocampus of intravenously administered MPEPy. In vivo EEG studies demonstrated that these mGlu5 PAMs have marked wake-promoting properties but little in the way of rebound hypersomnolence. In contrast, the previously described mGlu5 PAMs CDPPB and ADX47273 showed relatively poor evidence of in vivo target engagement in either receptor occupancy assays or EEG disturbance. Wake-promoting doses of LSN2463359 and LSN2814617 attenuated deficits in performance induced by the competitive NMDA receptor antagonist SDZ 220,581 in two tests of operant behaviour: the variable interval 30 s task and the DMTP task. These effects were lost if the dose of either compound extended into the range which disrupted performance in the baseline DMTP task. However, the improvements in response accuracy induced by the mGlu5 potentiators in SDZ 220,581-treated rats were not delay-dependent and, therefore, perhaps more likely reflected optimization of general arousal than specific beneficial effects on discrete cognitive processes. The systematic profiling of LSN2463359 and LSN2814617 alongside other previously described molecules will help determine more precisely how mGlu5 potentiator pharmacology might provide therapeutic benefit.
This article is part of a Special Issue entitled ‘Cognitive Enhancers’.
► Two novel mGlu5 potentiators are described, LSN2463359 and LSN2814617. ► Both compounds show high in vitro potency and low curve shift ratios. ► Brain penetrance and MPEPy displacement in vivo was dose-dependent. ► Both compounds markedly increased wakefulness without disrupting operant behaviour. ► Both compounds attenuated NMDA antagonist impairments of operant behaviour.
A facile one-step synthesis of spiro4.5deca-6,9-diene-2,8-dione(1) from p-methoxyphenylacetyl chloride via a Friedel-Crafts acylation followed by ring closure is reported.
Background: The peroxisome proliferator-activated receptors (PPARs) were cloned as orphan members of the nuclear receptor superfamily of transcription factors. The identification of subtype-selective ...ligands for PPARα and PPARγ has led to the discovery of their roles in the regulation of lipid metabolism and glucose homeostasis. No subtype-selective PPARδ ligands are available and the function of this subtype is currently unknown.
Results: A three-component library was designed in which one of the monomers was biased towards the PPARs and the other two monomers were chosen to add chemical diversity. Synthesis and screening of the library resulted in the identification of pools with activity on each of the PPAR subtypes. Deconvolution of the pools with the highest activity on PPARδ led to the identification of GW 2433 as the first high-affinity PPARδ ligand.
3HGW 2433 is an effective radioligand for use in PPARδ competition-binding assays.
Conclusions: The synthesis of biased chemical libraries is an efficient approach to the identification of lead molecules for members of sequence-related releptor families. This approach is well suited to the discovery of small-molecule ligands for orphan receptors.
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