In This Issue Cite This: ACS Med. Chem. Lett. 2019, 10, 227−227
ACS Med. Chem. Lett. 2019.10:227-227. Downloaded from pubs.acs.org by 85.202.194.28 on 03/14/19. For personal use only.
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MODULATION OF AMPA RECEPTOR GATING BY THE ANTICONVULSANT DRUG, PERAMPANEL AMPA receptors are postsynaptic, transmembrane, ionotropic glutamate receptors distributed throughout the CNS that rapidly transmit excitatory signals before quickly desensitizing. Interest in modulation of these receptors has increased with the development of ligands that temper the activity of the signaling pathway as part of anticonvulsant therapy. In this Featured Letter, Nowak and co-workers (DOI: 10.1021/acsmedchemlett.8b00322) elucidate insights related to the mechanistic pharmacology behind the antiepileptic activity of perampanel, a selective, negative allosteric AMPA receptor ligand. Using single AMPA receptor channel patchclamp recordings with varying concentrations of perampanel, in combination with published crystallographic data of perampanel bound to each of four AMPA receptor subunits, the group illustrates the correlation between binding site occupancy and receptor conductance levels. While high concentrations of the ligand likely maximized binding site occupancy, serving as a molecular “off-switch”, these studies suggest that the greatest therapeutic value of negative allosteric AMPA receptor modulators may be achieved during partial inhibition. In these circumstances, less than 1:1 binding occupancy may permit reduced neuronal receptor activity that may be beneficial during seizures.
in compound dissolution. While this effort was insufficient to propel VU2957 into Investigational New Drug-enabling studies, VU2957 serves as a valuable mGlu4 prototype and formulation case study in the race to develop clinically successful mGlu4 PAMs based on this structural framework.
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ATORVASTATIN (LIPITOR) BY MCR The highly convergent and efficient nature of multicomponent transformations holds tremendous appeal in the pursuit of the ideal synthesis. These processes, generally defined by the onestep combination of three or more starting materials to yield a product containing structural architecture of each reagent, have been widely employed to build various heterocycles, including several clinically investigated and marketed drugs. Dömling and co-workers reveal in their recent Note (DOI: 10.1021/acsmedchemlett.8b00579) the application of the fourcomponent Ugi reaction to the synthesis of the cholesterollowering blockbuster drug, Atorvastatin (Lipitor). The authors review the advantages and shortcomings of published routes while implementing their own approach which intersects with an established, regioselective 1,3-dipolar münchnone cycloaddition en route to the product and showcases an overall reduced synthetic step count. The synthesis highlights the utility of multicomponent reaction assembly in drug discovery and its potential in preparing diversified libraries and tool compounds based on successful drug structures.
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DISCOVERY OF VU2957 (VALIGLURAX): AN mGlu4 POSITIVE ALLOSTERIC MODULATOR EVALUATED AS A PRECLINICAL CANDIDATE FOR THE TREATMENT OF PARKINSON’S DISEASE Parkinson’s disease (PD), a neurodegenerative disorder for which there is no cure, is predominately marked by the gradual, region-specific loss of dopamine-producing neurons in the brain. The emergence of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 4 (mGlu4) has been an important milestone in revealing new therapeutic targets for PD. In their Letter, Lindsley et al. (DOI: 10.1021/acsmedchemlett.8b00426) describe the development and preclinical evaluation of orally available Valiglurax (VU2957), an Nlinked heterobicyclic compound that selectively and potently potentiated mGlu4, had low CYP metabolic liability, and demonstrated promising CNS-penetration and pharmacokinetic properties in rodents and nonhuman primates. To address solubility limitations and execute dose escalation studies, the team implemented a spray-dried dispersion strategy to formulate VU2957, resulting in a 40-fold increase © 2019 American Chemical Society
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Special Issue: Allosteric Modulation of Ionotropic Glutamate Receptors Published: March 14, 2019 227
DOI: 10.1021/acsmedchemlett.9b00072 ACS Med. Chem. Lett. 2019, 10, 227−227
