Bihaptenes : de l'allergie a la tolerance

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

AMPA Antagonists: From bench to bedside.

AMPA receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system. They also play a key role in synaptic plasticity in the CNS and in memory processes. They may thereby have utility in a number of CNS disorders. In recent years several classes of AMPA receptor antagonists, both competitive and non-competitive, have been reported in the literature. Compounds that present a number of advantages in terms of potency, selectivity and pharmacokinetic properties are currently undergoing clinical evaluation. First successful clinical results in the treatment of epilepsy, the treatment of migraine, as analgesics as well as for the treatment of hyperalgesia and allodynia, have been reported. In the near future, the most important applications for the AMPA receptor antagonists will probably be as neuroprotectant in various neurodegenerative diseases. The present perspective covers recent history of competitive and non-competitive AMPA receptor antagonists design, clinical results obtained with these compounds and emerging therapeutic opportunities

AMPA receptor antagonists: potential therapeutic applications.

The current review will focus on the recent patents for AMPA receptor antagonists and their claims, evidence for their therapeutic effectiveness in the treatment of epilepsy and their potential role in psychiatric and neurodegenerative disorders. It will also highlight the proposed mechanisms of action and the implications thereof for our current understanding of the biomolecular basis of these pathologies. It will conclude with a summary of what we know, but also point out the remaining uncertainties, especially as this relates to the claims in the patent under discussion

Discovery of novel non-peptidic beta-alanine piperazine amide derivatives and their optimization to achiral, easily accessible, potent and selective somatostatin sst1 receptor antagonists.

Structural simplification of the core moieties of obeline and ergoline somatostatin sst(1) receptor antagonists, followed by systematic optimization, led to the identification of novel, highly potent and selective sst(1) receptor antagonists. These achiral, non-peptidic compounds are easily prepared and show promising PK properties in rodents

Quinazolinedione sulfonamides: A Novel Class of Competitive AMPA Receptor Antagonists with Oral Activity

Quinazoline-2,4-diones with a sulfonamide group attached to the N(3) ring atom constitute a novel class of competitive AMPA receptor antagonists. One of the synthesized compounds, 28, shows nanomolar receptor affinity, whereas other examples of the series display oral anticonvulsant activity in animal models

Design and synthesis of Selurampanel, a novel orally active and competitive AMPA receptor antagonist.

A series of potent quinazolinedione sulfonamide AMPA receptor antagonists were designed and synthesized. The SAR and in vivo activity of the series were investigated. In particular, compound 1S (Selurampanel) has shown excellent oral potency against MES-induced generalized tonic-clonic seizures in rodents. The X-ray structure of Selurampanel bound to AMPA was also obtained

Design and Synthesis of Selective and Potent Orally Active S1P5 Agonists

Putting the brakes on demyelination: Fingolimod (FTY720) was recently shown to significantly decrease relapse rates in patients with multiple sclerosis. This drug attenuates the trafficking of harmful T-cells entering the brain by regulating sphingosine-1-phosphate (S1P) receptors. We designed, synthesized, evaluated 2H-phthalazin-1-one derivatives (e.g., 1 L) as selective S1P5 receptor agonists; these compounds are highly potent and selective, with good PK properties, and significant activity in oligodendrocytes

6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists

A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED50 of 5.5 mg/kg in an animal model of anticonvulsant activity after oral dosage

The Crystal structure of the cancer osaka thyroid kinase reveals an unexpected kinase domain fold

Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Cancer Osaka Thyroid (COT) kinase, also known as mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and tumor progression locus 2 (Tpl-2), is a Serine-Threonine (ST) kinase and is a key regulator in the production of proinflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT kinase has been identified as an attractive target for pharmaceutical research that is directed at the discovery of orally available, selective and potent inhibitors for the treatment of autoimmune disorders. The production of monomeric, recombinant COT kinase has proven to be very difficult and issues with solubility and stability of the enzyme have hampered the discovery and optimization of potent and selective inhibitors. We developed a protocol for the production of recombinant human COT kinase that yields pure and highly active enzyme in sufficient yields for biochemical and structural studies. The quality of the enzyme allowed us to establish a robust in vitro phosphorylation assay for the efficient biochemical characterization of COT kinase inhibitors and to determine the X-ray co-crystal structures of the COT kinase domain in complex with two ATP-binding site inhibitors. The structures presented in this publication reveal two distinct ligand binding modes and a unique kinase domain architecture that has not been observed previously. The glycine-rich loop contains a 15 amino acid insert that forms a β-hairpin structure and partially covers the ATP-binding site cleft, which – together with the structurally versatile active site – significantly impacts the design of potent, low-molecular weight COT inhibitors