Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2024; 124(03): 203-222
DOI: 10.1055/a-2211-5202

New Technologies, Diagnostic Tools and Drugs

Diphenyl-tetrazol-propanamide Derivatives Act as Dual-Specific Antagonists of Platelet CLEC-2 and Glycoprotein VI

¹Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

²Institute of Advanced Biosciences, Tokai University, Hiratsuka, Kanagawa, Japan

,

Yoshiko Shinozaki

³Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan

,

Sanae Ogiwara

³Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan

,

Riko Miyagasako

³Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan

,

Ayumi Sasaki

³Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan

,

Junko Kato

³Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan

,

Yusuke Suzuki

³Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan

,

Natsuko Fukunishi

³Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan

,

Yoshinori Okada

³Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan

,

Takeshi Saito

¹Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

,

Yumi Iida

³Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan

,

Misaki Higashiseto

³Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa, Japan

,

Haruchika Masuda

⁴Department of Physiology, Tokai University School of Medicine, Shimokasuya, Isehara, Kanagawa, Japan

,

Eiichiro Nagata

⁵Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan

,

Kazuhito Gotoh

⁶Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

,

Mari Amino

¹Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

,

Tomoatsu Tsuji

¹Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

,

Seiji Morita

¹Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

,

Yoshihide Nakagawa

¹Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

,

Noriaki Hirayama

²Institute of Advanced Biosciences, Tokai University, Hiratsuka, Kanagawa, Japan

⁷The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan

,

Sadaki Inokuchi

¹Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

²Institute of Advanced Biosciences, Tokai University, Hiratsuka, Kanagawa, Japan

› Institutsangaben

Abstract

Background Platelet C-type lectin-like receptor 2 (CLEC-2) induces platelet activation and aggregation after clustering by its ligand podoplanin (PDPN). PDPN, which is not normally expressed in cells in contact with blood flow, is induced in inflammatory immune cells and some malignant tumor cells, thereby increasing the risk of venous thromboembolism (VTE) and tumor metastasis. Therefore, small-molecule compounds that can interfere with the PDPN–CLEC-2 axis have the potential to become selective antiplatelet agents.

Methods and Results Using molecular docking analysis of CLEC-2 and a PDPN–CLEC-2 binding-inhibition assay, we identified a group of diphenyl-tetrazol-propanamide derivatives as novel CLEC-2 inhibitors. A total of 12 hit compounds also inhibited PDPN-induced platelet aggregation in humans and mice. Unexpectedly, these compounds also fit the collagen-binding pocket of the glycoprotein VI molecule, thereby inhibiting collagen interaction. These compounds also inhibited collagen-induced platelet aggregation, and one compound ameliorated collagen-induced thrombocytopenia in mice. For clinical use, these compounds will require a degree of chemical modification to decrease albumin binding.

Conclusion Nonetheless, as dual activation of platelets by collagen and PDPN-positive cells is expected to occur after the rupture of atherosclerotic plaques, these dual antagonists could represent a promising pharmacophore, particularly for arterial thrombosis, in addition to VTE and metastasis.

Keywords

Keywords

tumor metastasis - thrombosis - stroke - myocardial infarction

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