115186-33-9Relevant articles and documents
Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L
Aggarwal, Anupriya,Ashhurst, Anneliese S.,Bedding, Max J.,Beretta, Laura,Drelich, Aleksandra,Gerwick, William H.,Hook, Vivian,Larance, Mark,Li, Linfeng,McKerrow, James H.,Meek, Thomas D.,O'Donoghue, Anthony J.,Payne, Richard J.,Pwee, Dustin,Skinner, Danielle,Stoye, Alexander,Tang, Arthur H.,Tseng, Chien-Te,Turville, Stuart,Yoon, Michael C.,Fajtová, Pavla
supporting information, (2021/11/18)
Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is a promising drug target for novel antivirals against SARS-CoV-2. The marine natural product gallinamide A and several synthetic analogues were identified as potent inhibitors of cathepsin L with IC50 values in the picomolar range. Lead molecules possessed selectivity over other cathepsins and alternative host proteases involved in viral entry. Gallinamide A directly interacted with cathepsin L in cells and, together with two lead analogues, potently inhibited SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range. Reduced antiviral activity was observed in cells overexpressing transmembrane protease, serine 2 (TMPRSS2); however, a synergistic improvement in antiviral activity was achieved when combined with a TMPRSS2 inhibitor. These data highlight the potential of cathepsin L as a COVID-19 drug target as well as the likely need to inhibit multiple routes of viral entry to achieve efficacy.
Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents
Jastaniah, Ammar,Gaisina, Irina N.,Knopp, Rachel C.,Thatcher, Gregory R. J.
, p. 2280 - 2285 (2020/09/23)
Calpain inhibitors have been proposed as drug candidates for neurodegenerative disorders, with ABT-957 entering clinical trials for Alzheimer's disease and mild cognitive impairment. The structure of ABT-957 was very recently disclosed, and trials were te
Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding
Deng, Hui,Kooijman, Sander,Van Den Nieuwendijk, Adrianus M. C. H.,Ogasawara, Daisuke,Van der Wel, Tom,Van Dalen, Floris,Baggelaar, Marc P.,Janssen, Freek J.,Van Den Berg, Richard J. B. H. N.,Den Dulk, Hans,Cravatt, Benjamin F.,Overkleeft, Herman S.,Rensen, Patrick C. N.,Van der Stelt, Mario
supporting information, p. 428 - 440 (2017/04/26)
Triazole ureas constitute a versatile class of irreversible inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2-AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4-substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5-position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets.