1,3,5‐Trisubstituted Pyrazoles as Potent Negative Allosteric Modulators of the mGlu_2/3 Receptors

Abstract

The metabotropic glutamate subtype2 (mGlu 2 )r eceptor is ap resynaptic membrane receptor distributed widely in brain that providesf eedback inhibitory control of glutamate release. Inhibition of the mGlu 2 receptor function with an egative allosteric modulator (NAM) enhances activity-dependent glutamate release, which may be of therapeutic benefitf or the treatment of neurologicala nd psychiatric disorders. An attractive pyrazole hit was identified after ah igh-throughput screening (HTS) campaign. The evolution of this hit is describedb y structure-activity relationship (SAR) studies on specific parts of the molecule. From near micromolar potency we could obtain compounds with single-digit nanomolar activity in the mGlu 2 NAM GTPgSa ssay.I na ddition to SAR on in vitro potency, am ore detailed overview is given with as pecific set of compounds on the excellent agreement between in vitro potency, free brain concentration, and ex vivo mGlu 2 receptor occupancy.F inally,t oo btain improved drug-like compounds, plans for future research are suggested towardi ncreasing free brain concentration while maintaining high in vitro potency.Glutamate is considered the most important excitatory neurotransmitter in the vertebrate brain.I tt riggers and modulates synaptic activity by interacting on two differentf amilies of receptors:l igand-gated ion channels, known as ionotropic glutamate receptors (iGlu), and Gprotein-coupled glutamate receptors termed metabotropic glutamate (mGlu) receptors. [1] These mGlu receptors can be divided into three different groups based on their sequence homology,p harmacological profile, and preferential signal transductionp athway:g roup I( mGlu 1 and mGlu 5 ), group II (mGlu 2 and mGlu 3 ), and group III (mGlu 4 , mGlu 6 ,m Glu 7 ,a nd mGlu 8 ). [2] The mGlu 2 receptori se xpressed on presynaptic nerve terminals just outside the synaptic cleft where it reduces excitatory neurotransmission in an activity-dependentm anner due to its negativef eedback regulation on the release of glutamate into the synapse. [3] Experimental studies suggest that mGlu receptors play an important role in brain functions relatedtoinformation storage and plasticity and may hold the key to the longevity and stability of synaptic plasticity underlying long-termm emory.P articularly group II mGlu receptors have been associatedw ith regulation of cognitive processes,m ostly in cortico-cortical and/or hippocampal regions. An egative allosteric modulator (NAM) at mGlu 2/3 receptors has been shown to increasel ongterm potentiation (LTP) in the dentate gyrus of hippocampal slices in vitro. [4] This suggests af avorable influence on learning and memory,a sc onfirmed by effectso fs uch compounds on long-term recognition memory,w orking memory,c ognitive flexibility,s patial learningo rs ocial recognition memory in various paradigms that assess cognitive functioninr odents.Several chemotypes of negative allostericm odulators of the group II mGlu receptors have been described, mainly by researchersa tH offmann-La Roche, with di...

DFT Study of Regio- and Stereoselective 13DC Reaction between Diazopropane and Substituted Chalcone Derivatives: Molecular Docking of Novel Pyrazole Derivatives as Anti-Alzheimer’s Agents

“…Quinoline, pyrazole, oxadiazole, thiophene, diazepine and others were the most studied heterocyclic compounds in organic synthesis and drug discovery [ 3 , 4 , 5 ]. Taking the case of pyrazole-based pharmaceuticals, they treat a wide array of diseases and conditions including obesity [ 6 , 7 ], diabetes [ 8 ], cancer [ 9 ], microbial [ 10 ] and viral infections [ 11 ], pain and inflammation [ 12 ] and many neurological disorders [ 13 ]. As well, the oxadiazole derivatives have attracted a wide attention of chemists in search for new therapeutic molecules and constitute an important class of compounds with a wide range of biological properties.…”

Synthesis of 1,3,5-trisubstituted pyrazolesvia1,3-dipolar cycloaddition of nitrile imines with ninhydrin-derived Morita–Baylis–Hillman carbonates

“…4 Other compounds also display a variety of important biological activities, such as anti-malarial and anti-cancer. 5 Due to their momentous and potent biological activities and the numerous possibilities for structural diversification, more and more organic and medicinal chemists are being attracted to developing effective and advanced methodologies for the construction of pyrazole scaffolds. 6…”

DFT study of regio- and stereo-selective 13DC reaction between diazopropane and substituted chalcone derivatives: Molecular docking of novel pyrazole derivatives as Anti-Alzheimer’s Agents

“…Quinoline, Pyrazole, oxadiazole, thiophene, diazepine… were the most studied of heterocyclic compounds in organic synthesis and in drug discovery (Hosseini and Bayat, 2018;Musiol, 2017;Shah and Verma, 2018). Taking the case of pyrazole that's based pharmaceuticals treat a wide array of diseases and conditions including obesity (Chang et al, 2013;Sharma et al, 2015), diabetes (Datar and Jadhav, 2015), cancer (Bennani et al, 2020), microbial (B'Bhatt and Sharma, 2017) and viral infections (Pancic et al, 1981), pain and inflammation (Mantzanidou et al, 2021) and many neurological disorders (Van Gool et al, 2017).…”