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Metabotropic glutamate 2/3 (mGlu 2/3 ) receptors are of considerable interest owing to their role in modulating glutamate transmission via presynaptic, postsynaptic and glial mechanisms. As part of our ongoing efforts to identify novel ligands for these receptors, we have discovered (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid; (LY3020371), a potent and selective orthosteric mGlu 2/3 receptor antagonist. In this account, we characterize the effects of LY3020371 in membranes and cells expressing human recombinant mGlu receptor subtypes as well as in native rodent and human brain tissue preparations, providing important translational information for this molecule. In membranes from cells expressing recombinant human mGlu 2 and mGlu 3 receptor subtypes, LY3020371.HCl competitively displaced binding of the mGlu 2/3 agonist ligand [ 3 H]-459477 with high affinity (hmGlu 2 K i = 5.26 nM; hmGlu 3 Ki = 2.50 nM). In cells expressing hmGlu 2 receptors, LY3020371.HCl potently blocked mGlu 2/3 agonist (DCG-IV)-inhibited, forskolin-stimulated cAMP formation (IC 50 = 16.2 nM), an effect that was similarly observed in hmGlu 3 -expressing cells (IC 50 = 6.21 nM). Evaluation of LY3020371 in cells expressing the other human mGlu receptor subtypes revealed high mGlu 2/3 receptor selectivity. In rat native tissue assays, LY3020371 demonstrated effective displacement of [ 3 H]-459477 from frontal cortical membranes (K i = 33 nM), and functional antagonist activity in cortical synaptosomes measuring both the reversal of agonist-suppressed second messenger production (IC 50 = 29 nM) and agonist-inhibited, K + -evoked glutamate release (IC 50 = 86 nM). Antagonism was fully recapitulated in both primary cultured cortical neurons where LY3020371 blocked agonist-suppressed spontaneous Ca 2+ oscillations (IC 50 = 34 nM) and in an intact hippocampal slice preparation (IC 50 = 46 nM). Functional antagonist activity was similarly demonstrated in synaptosomes prepared from epileptic human cortical or hippocampal tissues, suggesting a translation of the mGlu 2/3 antagonist pharmacology from rat to human. Intravenous dosing of LY3020371 in rats led to cerebrospinal fluid drug levels that are expected to effectively block mGlu 2/3 receptors in vivo. Taken together, these results establish LY3020371 as an important new pharmacological tool for studying mGlu 2/3 receptors in vitro and in vivo. This article is part of the Special Issue entitled ‘Metabotropic Glutamate Receptors, 5 years on’. [ABSTRACT FROM AUTHOR]

Continued SAR optimization of a series of 3-methylpyridine-2-carbonyl amino-2,4-dimethyl-benzoic acid led to the selection of compound 4f for clinical studies. Compound 4f showed an IC 50 of 123 nM for inhibition of PGE2-induced TNFα reduction in an ex vivo LPS-stimulated human whole blood assay (showing >10-fold increase over clinical compound CJ-023,423). Pharmacokinetic profile, selectivity and in vivo efficacy comparing 4f to NSAID diclofenac in the monoiodoacetic acid (MIA) pain model and adjuvant induced arthritis (AIA) inflammatory model are included. [ABSTRACT FROM AUTHOR]

Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles. [ABSTRACT FROM AUTHOR]

A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically relevant human whole blood assay was identified. Selectivity and pharmacokinetic profiles of this compound are discussed. [ABSTRACT FROM AUTHOR]

Abstract: A population-based case-control study was conducted in a high-risk area (Dafeng) and a low-risk area (Ganyu) of Jiangsu province, China. In this analysis, the population attributable fraction (PAF) was calculated to quantify the etiology of risk factors; the relative attributable risk (RAR) was applied to explore how much of the incidence difference could be explained by variations in the distribution of risk factors. Results showed that unhealthy lifestyles accounted for a high fraction of esophageal cancer in China. Dissimilar distribution of several lifestyle factors, together with hereditary variations may be largely responsible for the incidence difference between areas. [Copyright &y& Elsevier]

EP 4 is a prostaglandin E 2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP 4 antagonists which reverses PGE 2 -induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound ( 6 ) has been selected for potential clinical studies. EP 4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included. [ABSTRACT FROM AUTHOR]