Design and Evaluation of Heterobivalent PAR1-PAR2 Ligands As Antagonists of Calcium Mobilization

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Jan 19

PMID 30655958

Citations 8

Authors

Mark W Majewski

Disha M Gandhi

Ricardo Rosas Jr

Revathi Kodali

Leggy A Arnold

Chris Dockendorff

Affiliations

Soon will be listed here.

Abstract

A novel class of bivalent ligands targeting putative protease-activated receptor (PAR) heteromers has been prepared based upon reported antagonists for the subtypes PAR1 and PAR2. Modified versions of the PAR1 antagonist RWJ-58259 containing alkyne adapters were connected via cycloaddition reactions to azide-capped polyethylene glycol (PEG) spacers attached to imidazopyridazine-based PAR2 antagonists. Initial studies of the PAR1-PAR2 antagonists indicated that they inhibited G alpha q-mediated calcium mobilization in endothelial and cancer cells driven by both PAR1 and PAR2 agonists. Compounds of this novel class hold promise for the prevention of restenosis, cancer cell metastasis, and other proliferative disorders.

Citing Articles

Protease-activated receptors in vascular smooth muscle cells: a bridge between thrombo-inflammation and vascular remodelling.

Habibi A, Ruf W, Schurgers L Cell Commun Signal. 2025; 23(1):57.

PMID: 39891111 PMC: 11786455. DOI: 10.1186/s12964-025-02066-6.

Protease-Activated Receptor 2 in inflammatory skin disease: current evidence and future perspectives.

Fan M, Fan X, Lai Y, Chen J, Peng Y, Peng Y Front Immunol. 2024; 15:1448952.

PMID: 39301020 PMC: 11410643. DOI: 10.3389/fimmu.2024.1448952.

An orthosteric/allosteric bivalent peptide agonist comprising covalently linked protease-activated receptor-derived peptides mimics in vitro and in vivo activities of activated protein C.

Healy L, Fernandez J, Aiolfi R, Mosnier L, Griffin J J Thromb Haemost. 2024; 22(7):2039-2051.

PMID: 38670314 PMC: 11610403. DOI: 10.1016/j.jtha.2024.04.007.

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands.

Shpakov A Int J Mol Sci. 2023; 24(7).

PMID: 37047169 PMC: 10094638. DOI: 10.3390/ijms24076187.

Protease-activated receptors in health and disease.

Peach C, Edgington-Mitchell L, Bunnett N, Schmidt B Physiol Rev. 2022; 103(1):717-785.

PMID: 35901239 PMC: 9662810. DOI: 10.1152/physrev.00044.2021.

References

OBrien P, Prevost N, Molino M, Hollinger M, Woolkalis M, Woulfe D . Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1. J Biol Chem. 2000; 275(18):13502-9. DOI: 10.1074/jbc.275.18.13502. View

Zhang H, Derian C, Andrade-Gordon P, Hoekstra W, McComsey D, White K . Discovery and optimization of a novel series of thrombin receptor (par-1) antagonists: potent, selective peptide mimetics based on indole and indazole templates. J Med Chem. 2001; 44(7):1021-4. DOI: 10.1021/jm000506s. View

Damiano B, Derian C, Maryanoff B, Zhang H, Gordon P . RWJ-58259: a selective antagonist of protease activated receptor-1. Cardiovasc Drug Rev. 2003; 21(4):313-26. DOI: 10.1111/j.1527-3466.2003.tb00124.x. View

Shi X, Gangadharan B, Brass L, Ruf W, Mueller B . Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis. Mol Cancer Res. 2004; 2(7):395-402. View

Chan T, Hilgraf R, Sharpless K, Fokin V . Polytriazoles as copper(I)-stabilizing ligands in catalysis. Org Lett. 2004; 6(17):2853-5. DOI: 10.1021/ol0493094. View

Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A . PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell. 2005; 120(3):303-13. DOI: 10.1016/j.cell.2004.12.018. View

Daniels D, Lenard N, Etienne C, Law P, Roerig S, Portoghese P . Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc Natl Acad Sci U S A. 2005; 102(52):19208-13. PMC: 1323165. DOI: 10.1073/pnas.0506627102. View

Vu T, Hung D, Wheaton V, Coughlin S . Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991; 64(6):1057-68. DOI: 10.1016/0092-8674(91)90261-v. View

Krishnamurthy V, Semetey V, Bracher P, Shen N, Whitesides G . Dependence of effective molarity on linker length for an intramolecular protein-ligand system. J Am Chem Soc. 2007; 129(5):1312-20. PMC: 2535942. DOI: 10.1021/ja066780e. View

10.

Corbeil C, Englebienne P, Moitessier N . Docking ligands into flexible and solvated macromolecules. 1. Development and validation of FITTED 1.0. J Chem Inf Model. 2007; 47(2):435-49. DOI: 10.1021/ci6002637. View

11.

Kaufmann R, Rahn S, Pollrich K, Hertel J, Dittmar Y, Hommann M . Thrombin-mediated hepatocellular carcinoma cell migration: cooperative action via proteinase-activated receptors 1 and 4. J Cell Physiol. 2007; 211(3):699-707. DOI: 10.1002/jcp.21027. View

12.

Chackalamannil S, Wang Y, Greenlee W, Hu Z, Xia Y, Ahn H . Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem. 2008; 51(11):3061-4. DOI: 10.1021/jm800180e. View

13.

Meldal M, Tornoe C . Cu-catalyzed azide-alkyne cycloaddition. Chem Rev. 2008; 108(8):2952-3015. DOI: 10.1021/cr0783479. View

14.

Kaufmann R, Mussbach F, Henklein P, Settmacher U . Proteinase-activated receptor 2-mediated calcium signaling in hepatocellular carcinoma cells. J Cancer Res Clin Oncol. 2010; 137(6):965-73. DOI: 10.1007/s00432-010-0961-1. View

15.

Chieng-Yane P, Bocquet A, Letienne R, Bourbon T, Sablayrolles S, Perez M . Protease-activated receptor-1 antagonist F 16618 reduces arterial restenosis by down-regulation of tumor necrosis factor α and matrix metalloproteinase 7 expression, migration, and proliferation of vascular smooth muscle cells. J Pharmacol Exp Ther. 2010; 336(3):643-51. DOI: 10.1124/jpet.110.175182. View

16.

Wiviott S, Flather M, ODonoghue M, Goto S, Fitzgerald D, Cura F . Randomized trial of atopaxar in the treatment of patients with coronary artery disease: the lessons from antagonizing the cellular effect of Thrombin–Coronary Artery Disease Trial. Circulation. 2011; 123(17):1854-63. DOI: 10.1161/CIRCULATIONAHA.110.001404. View

17.

Shonberg J, Scammells P, Capuano B . Design strategies for bivalent ligands targeting GPCRs. ChemMedChem. 2011; 6(6):963-74. DOI: 10.1002/cmdc.201100101. View

18.

Sevigny L, Austin K, Zhang P, Kasuda S, Koukos G, Sharifi S . Protease-activated receptor-2 modulates protease-activated receptor-1-driven neointimal hyperplasia. Arterioscler Thromb Vasc Biol. 2011; 31(12):e100-6. PMC: 3241440. DOI: 10.1161/ATVBAHA.111.238261. View

19.

Dockendorff C, Aisiku O, VerPlank L, Dilks J, Smith D, Gunnink S . Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor. ACS Med Chem Lett. 2012; 3(3):232-237. PMC: 3297361. DOI: 10.1021/ml2002696. View

20.

Xu L, Josan J, Vagner J, Caplan M, Hruby V, Mash E . Heterobivalent ligands target cell-surface receptor combinations in vivo. Proc Natl Acad Sci U S A. 2012; 109(52):21295-300. PMC: 3535626. DOI: 10.1073/pnas.1211762109. View