Polypharmacology - Foe or Friend?

被引：361

作者：

Peters, Jens-Uwe ^{[1
]}

机构：

[1] F Hoffmann La Roche Ltd, pRED, Pharma Res & Early Dev, Discovery Chem, CH-4070 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 22期

关键词：

TARGET-DIRECTED LIGANDS; DRUG DISCOVERY; MOLECULAR-BASIS; PHARMACOLOGICAL-TREATMENT; SELECTIVE OPTIMIZATION; COMPOUND PROMISCUITY; NETWORK PHARMACOLOGY; MEDICINAL CHEMISTRY; MULTITARGET DRUGS; MULTIPLE LIGANDS;

D O I：

10.1021/jm400856t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.

引用

页码：8955 / 8971

页数：17

共 196 条

[1] 'Clean' or 'dirty' - Just how selective do drugs need to be? [J].

Abbenante, Giovanni ;

Reid, Robert C. ;

Fairlie, David P. .

AUSTRALIAN JOURNAL OF CHEMISTRY, 2008, 61 (09) :654-660

[2] NETWORKING FOR NEW DRUGS [J].

Ainsworth, Claire .

NATURE MEDICINE, 2011, 17 (10) :1166-1168

[3] BW-A575C, A CHEMICALLY NOVEL AGENT WITH ANGIOTENSIN CONVERTING-ENZYME-INHIBITOR AND BETA-ADRENOCEPTOR-BLOCKING PROPERTIES [J].

ALLAN, G ;

CAMBRIDGE, D ;

HARDY, GW ;

FOLLENFANT, MJ .

BRITISH JOURNAL OF PHARMACOLOGY, 1987, 90 (03) :609-615

[4] Synthesis and evaluation of hybrid drugs for a potential HIV/AIDS-malaria combination therapy [J].

Aminake, Makoah N. ;

Mahajan, Aman ;

Kumar, Vipan ;

Hans, Renate ;

Wiesner, Lubbe ;

Taylor, Dale ;

de Kock, Carmen ;

Grobler, Anne ;

Smith, Peter J. ;

Kirschner, Marc ;

Rethwilm, Axel ;

Pradel, Gabriele ;

Chibale, Kelly .

BIOORGANIC & MEDICINAL CHEMISTRY, 2012, 20 (17) :5277-5289

[5] MOLECULAR-CONFORMATION AND BIOLOGICAL-ACTIVITY OF CENTRAL NERVOUS-SYSTEM ACTIVE-DRUGS [J].

ANDREWS, PR ;

LLOYD, EJ .

MEDICINAL RESEARCH REVIEWS, 1982, 2 (04) :355-393

[6]

[Anonymous], POLYPHARMACOLOGY DRU

[7] The influence of lipophilicity in drug discovery and design [J].

Arnott, John A. ;

Planey, Sonia Lobo .

EXPERT OPINION ON DRUG DISCOVERY, 2012, 7 (10) :863-875

[8] Kinase-likeness and kinase-privileged fragments: Toward virtual polypharmacology [J].

Aronov, Alex M. ;

McClain, Brian ;

Moody, Cameron Stuver ;

Murcko, Mark A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (05) :1214-1222

[9] Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent [J].

Artis, Dean R. ;

Lin, Jack J. ;

Zhang, Chao ;

Wang, Weiru ;

Mehra, Upasana ;

Perreault, Mylene ;

Erbe, David ;

Krupka, Heike I. ;

England, Bruce P. ;

Arnold, James ;

Plotnikov, Alexander N. ;

Marimuthu, Adhirai ;

Nguyen, Hoa ;

Will, Sarah ;

Signaevsky, Maxime ;

Kral, John ;

Cantwell, John ;

Settachatgull, Calvin ;

Yan, Douglas S. ;

Fong, Daniel ;

Oh, Angela ;

Shi, Shenghua ;

Womack, Patrick ;

Powell, Benjamin ;

Habets, Gaston ;

West, Brian L. ;

Zhang, Kam Y. J. ;

Milburn, Michael V. ;

Vlasuk, George P. ;

Hirth, K. Peter ;

Nolop, Keith ;

Bollag, Gideon ;

Ibrahim, Prabha N. ;

Tobin, James F. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (01) :262-267

[10] Drug repositioning: Identifying and developing new uses for existing drugs [J].

Ashburn, TT ;

Thor, KB .

NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (08) :673-683

← 1 2 3 4 5 6 7 8 9 10 →