In This Issue Cite This: ACS Med. Chem. Lett. 2018, 9, 159−160
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MULTITARGET-DIRECTED INHIBITORS AS A STRATEGY FOR ALZHEIMER’S DISEASE TREATMENT Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease that has defied traditional approaches directed at single drug targets. While the mechanistic basis for AD pathogenesis remains controversial, formation of neurotoxic tau fibrils and decreased production of the neurotransmitter acetylcholine are hallmarks of AD. In this issue, Jiang et al. (DOI: 10.1021/ acsmedchemlett.7b00463) report on multitarget inhibitors designed to prevent tau aggregation as well as restore neuronal acetylcholine levels by simultaneously blocking glycogen synthase-3β (GSK-3β) and human acetylcholinesterase (hAChE). The dual inhibitors were synthesized by strategically linking a pyridothiazole (GSK-3β ligand) with tacrine (hAChE ligand) based on X-ray crystal structures of each enzyme. Their best compound 2f possessed balanced nanomolar potency, inhibited tau phosphorylation in cell culture, restored memory function of mice, and demonstrated a useful safety profile as measured in several toxicological studies. These results highlight the advantages of polypharmacology for complex diseases like AD.
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MECHANISTIC STUDIES OF THE EFFECT OF ANTIVIRALS ON THE INFLUENZA M2 PROTON CHANNEL The clinical utility of the antiviral agents amantadine and rimantadine have been compromised by resistance due to mutation (S31N) in the influenza virus M2 proton channel. Additionally, drug target residence times are increasingly being recognized as critical parameters in drug discovery. In order to provide deeper insight into the mechanistic basis for the observed loss of activity, Drakopoulos et al. (DOI: 10.1021/ acsmedchemlett.7b00458) measured binding energies and kinetics of these compounds in conjunction with antiviral, functional assays of the proton channel, and molecular dynamic simulations. The authors showed the dissociation rate constants were dramatically increased in the mutant M2 proteins resulting in short residence times. Another findings was the classical functional assay used to initially screen M2 inhibitors
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DISCOVERY OF A STRESS-ACTIVATED PROTEIN KINASE INHIBITOR FOR LYMPHATIC FILARIASIS Lymphatic filariasis (elephantiasis) is a devastating neglected tropical disease caused by various species of roundworms (e.g., Brugia malayi). Although treatments are available (ivermectin and albendazole, both introduced more than 40 years ago), increased drug resistance and serious adverse effects warrant development of a new generation of antifilarial medicines. Using target class repurposing, Tummalapalli et al. (DOI: 10.1021/acsmedchemlett.7b00477) had previously identified a phenylpyrimdinyl isoxazole-based inhibitor of the human p38 kinase that had modest activity against a homologous kinase in B. malayi, termed Bm-MPK1, a pathogen effector responsible for counteracting host-induced oxidative stress. A focused structure−activity relationship campaign identified compound 15b with low nanomolar enzyme inhibition of Bm-MPK1 and corresponding outstanding antifilarial activity in a phenotypic motility assay, nearly 100-fold more potent than their lead compound. Further metabolic/pharmacokinetic profiling revealed 15b was orally bioavailable, achieving plasma levels above the in vitro IC50 for nearly 8 h. Analogue 15b thus represents a tool compound, which may be used to chemically validate Bm-MPK1 as a drug target in vivo. © 2018 American Chemical Society
Published: March 8, 2018 159
DOI: 10.1021/acsmedchemlett.8b00088 ACS Med. Chem. Lett. 2018, 9, 159−160
ACS Medicinal Chemistry Letters
In This Issue
may not identify potent compounds if they are slow binding. Collectively, these experiments provided a wealth of data providing a foundation for future efforts to improve this important class of antiviral agents.
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DOI: 10.1021/acsmedchemlett.8b00088 ACS Med. Chem. Lett. 2018, 9, 159−160
