Development of autotaxin inhibitors: A series of tetrazole cinnamides

Thomson, Christopher G.; Grand, Darren Le; Dowling, Mark R.; Beattie, David T.; Elphick, Lucy M.; Faller, Michael; Freeman, Mark; Hardaker, Elizabeth; Head, Victoria; Hemmig, R.; Hill, Johan C.; Lister, Andrew; Pascoe, David D.; Rieffel, S.; Shrestha, BP; Steward, Oliver; Zink, F.

doi:10.1016/j.bmcl.2020.127663

Cited by 2 publications

(3 citation statements)

References 12 publications

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“…It should be noted that cinnamide is a potential Michael receptor that could produce in vivo toxicity. 102,103 Therefore, the ability of these cinnamide-containing SMFIs to react with nucleophiles in vivo should be investigated in the future.…”

Section: Design and Discovery Of Small-molecule Fxia Inhibitorsmentioning

confidence: 99%

“…Cinnamide is commonly used in medicinal chemistry, and it can be found in the phenylalanine diamide-based SMFIs 5 , 8 , 9 , 13 , and 14 . It should be noted that cinnamide is a potential Michael receptor that could produce in vivo toxicity. , Therefore, the ability of these cinnamide-containing SMFIs to react with nucleophiles in vivo should be investigated in the future.…”

Section: Design and Discovery Of Small-molecule Fxia Inhibitorsmentioning

confidence: 99%

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Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

et al. 2023

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Factor XIa (FXIa) in the intrinsic pathway of the coagulation process has been proven to be an effective and safe target for anticoagulant discovery with limited or no bleeding. Numerous small-molecule FXIa inhibitors (SMFIs) with various scaffolds have been identified in the early stages of drug discovery. They have served as the foundation for the recent discovery of additional promising SMFIs with improved potency, selectivity, and pharmacokinetic profiles, some of which have entered clinical trials for the treatment of thrombosis. After reviewing the coagulation process and structure of FXIa, this perspective discusses the rational or structure-based design, discovery, structure−activity relationships, and development of SMFIs disclosed in recent years. Strategies for identifying more selective and druggable SMFIs are provided, paving the way for the design and discovery of more useful SMFIs for anticoagulation therapy.

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Section: Design and Discovery Of Small-molecule Fxia Inhibitorsmentioning

confidence: 99%

Section: Design and Discovery Of Small-molecule Fxia Inhibitorsmentioning

confidence: 99%

Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

et al. 2023

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“…To improve the problem, SAR analysis was performed, and finally 83 (IC 50 = 8 nM, LPC) was obtained; the clearance rate in rat liver microsomes was 15 µL/min/mg. The authors originally designed on the basis of a type I inhibitor, assuming that the tetrazolium moiety penetrates deep into the Catalytic site; however, the crystal structure suggests that piperazine guides the benzyl group into the tunnel and that the cinnamic acid moiety is located in the hydrophobic pocket [97]. This suggests that we are not able to take the designed compounds for granted and should fully study them, which will also aid in obtaining a deeper understanding of the structure and function of ATX.…”

Section: Glpg1690-based Atx Inhibitorsmentioning

confidence: 99%

Design and Development of Autotaxin Inhibitors

Jia

et al. 2021

Pharmaceuticals

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Autotaxin (ATX) is the only enzyme of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP2) family with lysophospholipase D (lysoPLD) activity, which is mainly responsible for the hydrolysis of extracellular lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA can induce various responses, such as cell proliferation, migration, and cytokine production, through six G protein-coupled receptors (LPA1-6). This signaling pathway is associated with metabolic and inflammatory disorder, and inhibiting this pathway has a positive effect on the treatment of related diseases, while ATX, as an important role in the production of LPA, has been shown to be associated with the occurrence and metastasis of tumors, fibrosis and cardiovascular diseases. From mimics of ATX natural lipid substrates to the rational design of small molecule inhibitors, ATX inhibitors have made rapid progress in structural diversity and design over the past 20 years, and three drugs, GLPG1690, BBT-877, and BLD-0409, have entered clinical trials. In this paper, we will review the structure of ATX inhibitors from the perspective of the transformation of design ideas, discuss the advantages and disadvantages of each inhibitor type, and put forward prospects for the development of ATX inhibitors in the future.

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Development of autotaxin inhibitors: A series of tetrazole cinnamides

Cited by 2 publications

References 12 publications

Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

Design and Development of Autotaxin Inhibitors

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