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

被引：13

作者：

Majewski, Mark W. ^{[1
]}

Gandhi, Disha M. ^{[1
]}

Rosas, Ricardo, Jr. ^{[1
]}

Kodali, Revathi ^{[2
]}

Arnold, Leggy A. ^{[2
]}

Dockendorff, Chris ^{[1
]}

机构：

[1] Marquette Univ, Dept Chem, POB 1881, Milwaukee, WI 53201 USA

[2] Univ Wisconsin, Milwaukee Inst Drug Discovery, Dept Chem & Biochem, Milwaukee, WI 53211 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 01期

关键词：

Bivalent ligand; protease-activated receptor; PAR1; antagonist; PAR2; calcium mobilization; metastasis; restenosis; BIVALENT LIGANDS; RECEPTOR; PAR1; DISCOVERY; POTENT; TRANSACTIVATION; HETERODIMER; DEPENDENCE; AGONIST;

D O I：

10.1021/acsmedchemlett.8b00538

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：121 / 126

页数：11

共 40 条

[1] PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells [J].

Boire, A ;

Covic, L ;

Agarwal, A ;

Jacques, S ;

Sherifl, S ;

Kuliopulos, A .

CELL, 2005, 120 (03) :303-313

[2] Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway [J].

Bouwens, E. A. M. ;

Stavenuiter, F. ;

Mosnier, L. O. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2013, 11 :242-253

[3] Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity [J].

Chackalamannil, Samuel ;

Wang, Yuguang ;

Greenlee, William J. ;

Hu, Zhiyong ;

Xia, Yan ;

Ahn, Ho-Sam ;

Boykow, George ;

Hsieh, Yunsheng ;

Palamanda, Jairam ;

Agans-Fantuzzi, Jacqueline ;

Kurowski, Stan ;

Graziano, Michael ;

Chintala, Madhu .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (11) :3061-3064

[4] Polytriazoles as copper(I)-stabilizing ligands in catalysis [J].

Chan, TR ;

Hilgraf, R ;

Sharpless, KB ;

Fokin, VV .

ORGANIC LETTERS, 2004, 6 (17) :2853-2855

[5] Structural insight into allosteric modulation of protease-activated receptor 2 [J].

Cheng, Robert K. Y. ;

Fiez-Vandal, Cedric ;

Schlenker, Oliver ;

Edman, Karl ;

Aggeler, Birte ;

Brown, Dean G. ;

Brown, Giles A. ;

Cooke, Robert M. ;

Dumelin, Christoph E. ;

Dore, Andrew S. ;

Geschwindner, Stefan ;

Grebner, Christoph ;

Hermansson, Nils-Olov ;

Jazayeri, Ali ;

Johansson, Patrik ;

Leong, Louis ;

Prihandoko, Rudi ;

Rappas, Mathieu ;

Soutter, Holly ;

Snijder, Arjan ;

Sundstrom, Linda ;

Tehan, Benjamin ;

Thornton, Peter ;

Troast, Dawn ;

Wiggin, Giselle ;

Zhukov, Andrei ;

Marshall, Fiona H. ;

Dekker, Niek .

NATURE, 2017, 545 (7652) :112-+

[6] 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].

Chieng-Yane, Pauline ;

Bocquet, Arnaud ;

Letienne, Robert ;

Bourbon, Thierry ;

Sablayrolles, Sylvie ;

Perez, Michel ;

Hatem, Stephane Nicolas ;

Lompre, Anne-Marie ;

Le Grand, Bruno ;

David-Dufilho, Monique .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2011, 336 (03) :643-651

[7] Docking ligands into flexible and solvated macromolecules. 1. Development and validation of FITTED 1.0 [J].

Corbeil, Christopher R. ;

Englebienne, Pablo ;

Moitessier, Nicolas .

JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2007, 47 (02) :435-449

[8]

Damiano BP, 2003, CARDIOVASC DRUG REV, V21, P313

[9] Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series [J].

Daniels, DJ ;

Lenard, NR ;

Etienne, CL ;

Law, PY ;

Roerig, SC ;

Portoghese, PS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (52) :19208-19213

[10] PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury [J].

De Ceunynck, Karen ;

Peters, Christian G. ;

Jain, Abhishek ;

Higgins, Sarah J. ;

Aisiku, Omozuanvbo ;

Fitch-Tewfik, Jennifer L. ;

Chaudhry, Sharjeel A. ;

Dockendorff, Chris ;

Parikh, Samir M. ;

Ingber, Donald E. ;

Flaumenhaft, Robert .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (05) :E982-E991

← 1 2 3 4 →