LEKI WIELOCELOWE – NOWY PARADYGMAT  W PROJEKTOWANIU LEKÓW

Piotr Bojanowski; Piotr F. J. Lipiński; Paweł Czekała; Dariusz Plewczyński

doi:10.56782/pps.92

Data publikacji : 2013-02-28

Tom 11 Nr 1 (2013)

LEKI WIELOCELOWE – NOWY PARADYGMAT W PROJEKTOWANIU LEKÓW

Piotr Bojanowski

Piotr F. J. Lipiński

Paweł Czekała

Dariusz Plewczyński

DOI: https://doi.org/10.56782/pps.92

Abstrakt

Przez co najmniej ostatnie 20 lat w chemii leków panował paradygmat „jedna choroba, jeden gen, jeden cel molekularny, jeden lek". Rozwój biologii systemów i pogłębienie wiedzy o złożoności molekularnej chorób istotnie przesuwają proces terapeutyczny w kierunku leków oddziaływających na wiele celów molekularnych, tj. leków wielocelowych. W niniejszym artykule przedstawiamy teoretyczne i historyczne podstawy zamierzonej wielocelowości, w tym korzyści wypływające ze stosowania takich leków, oraz omawiamy zagadnienia poszukiwania związków wiodących wraz z optymalizacją parametrów farmakodynamicznych i farmakokinetycznych. Następnie przedstawiamy przegląd najnowszej literatury na temat różnych obszarów zastosowań leków wielocelowych oraz bieżących trendów teoretycznych.

Słowa kluczowe:

biologia systemów, polifarmakologia, leki wielocelowe, choroba Alzheimera, nowotwory, bioinformatyka, chemoinformatyka

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Bojanowski, P., Lipiński, P. F. J., Czekała, P., & Plewczyński, D. (2013). LEKI WIELOCELOWE – NOWY PARADYGMAT W PROJEKTOWANIU LEKÓW. Prospects in Pharmaceutical Sciences, 11(1), 1–10. https://doi.org/10.56782/pps.92

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Bibliografia

S. M. Paul, D. S. Mytelka, C. T. Dunwiddie, C. C. Persinger, B. H. Munos, S. R. Lindborg, A.L. Schacht, How to improve R&D productivity: the pharmaceutical industry’s grand challenge, Nat. Rev. Drug. Discov., 2010, 9, 203-214. DOI: https://doi.org/10.1038/nrd3078

M. Hu, K. Schultz, J. Sheu, D. Tschopp, The Innovation Gap in Pharmaceutical Drug Discovery & New Models for R&D Success, Kellogg School of Management, 2007.

L. J. S. Knutsen, Drug discovery management, small is still beautiful: Why a number of companies get it wrong, Drug Discov. Today, 2011, 16, 476-484. DOI: https://doi.org/10.1016/j.drudis.2011.04.002

B. C. Daniels, Y. J. Chen, J. P. Sethna, R. N. Gutenkunst, C. R. Myers., Sloppiness, robustness, and evolvability in systems biology, Curr. Opin. Biotechnol.2008, 19, 389-395. DOI: https://doi.org/10.1016/j.copbio.2008.06.008

M. D. Sadar, M. Hussain, N. Bruchovsky, Prostate cancer: molecular biology of early progression to androgen independence, Endocr. Relat. Cancer, 1999, 6, 487-502. DOI: https://doi.org/10.1677/erc.0.0060487

A. L. Hopkins, Network pharmacology: the next paradigm in drug discovery, Nat. Chem. Biol. 2008, 4, 682-690. DOI: https://doi.org/10.1038/nchembio.118

R. Morphy, Z. Rankovic, The Practice of Medicinal Chemistry, 549-571, pod redakcją: C. G. Wermuth, M. J. Bowker, H. Kubinyi, i wsp. Elsevier 2008. DOI: https://doi.org/10.1016/B978-0-12-374194-3.00027-5

E. Jenwitheesuk, J. A. Horst, K. L. Rivas, W. C. Van Voorhis, R. Samudrala, Novel paradigms for drug discovery: computational multitarget screening, Trends Pharmacol. Sci., 2008, 29, 62-71. DOI: https://doi.org/10.1016/j.tips.2007.11.007

B. Granger, S. Albu, The haloperidol story, Ann. Clin. Psychiatry, 2005, 17, 137-140. DOI: https://doi.org/10.1080/10401230591002048

R. Morphy, Z. Rankovic, Designed multiple ligands. An emerging drug discovery paradigm, J. Med. Chem. 2005, 48, 6523-6543. DOI: https://doi.org/10.1021/jm058225d

M. L. Lolli, C. Cena, C. Medana, L. Lazzarato, G. Morini, G. Coruzzi, S. Mananrini, R. Fruttero, A. Gasco, A New Class of Ibuprofen Derivatives with Reduced Gastrotoxicity, J. Med. Chem., 2001, 44, 3463-3468. DOI: https://doi.org/10.1021/jm0108799

Y. Kawanishi, S. Ishihara, T. Tsushima, K. Seno, M. Miyagoshi, S. Hagishita, M.Ishikawa, N. Shima, M. Shimamura, Y. Ishihara, Synthesis and pharmacological evaluation of highly potent dual histamine H2 and gastrin receptor antagonists, Bioorg. Med. Chem. Lett.1996, 6, 1427-1430. DOI: https://doi.org/10.1016/S0960-894X(96)00249-1

N. Toda, K. Tago, S. Marumoto, K. Takami, M. Ori, N. Yamada, K. Koyama, S. Naruto, K. Abe, R. Yamazaki, T. Hara, A. Aoyagi, Y. Abe, T. Kaneko, H. Kogen, A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease, Bioorg. Med. Chem., 2003, 11, 4389-4415. DOI: https://doi.org/10.1016/S0968-0896(03)00452-8

F. P. Bymastera, E. E. Beedlea, J. Findlayb, P. T. Gallagherb, J. H. Krushinskia, S. Mitchellb, D. W. Robertsona, D. C. Thompsona, L. Wallaceb, D. T. Wonga, Duloxetine (Cymbalta™), a dual inhibitor of serotonin and norepinephrine reuptake, Bioorg. Med. Chem. Lett.2003, 13, 447-4480. DOI: https://doi.org/10.1016/j.bmcl.2003.08.079

S. Nyberg, B. Eriksson, G. Oxenstierna, C. Halldin, L. Farde, Suggested Minimal Effective Dose of Risperidone Based on PET-Measured D2 and 5-HT2A Receptor Occupancy in Schizophrenic Patients, Am. J. Psychiatry, 1999, 156, 869-875. DOI: https://doi.org/10.1176/ajp.156.6.869

C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Freeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Deliv. Rev., 1997, 23, 3-25. DOI: https://doi.org/10.1016/S0169-409X(96)00423-1

R. Morphy, C. Kay, Z. Rankovic, From magic bullets to designed multiple ligands, Drug Discov. Today, 2004, 9, 641-651. DOI: https://doi.org/10.1016/S1359-6446(04)03163-0

R. Morphy, Z. Rankovic, Design of Multitarget Ligands, in Lead Generation Approaches in Drug Discovery, John Wiley & Sons, Inc., Hoboken, NJ, USA2010. DOI: https://doi.org/10.1002/9780470584170

M. L. Bolognesi, M. Rosini, V. Andrisano, M. Bartolini, A. Minarini, V. Tumiatti, C. Melchiorre, MTDL Design Strategy in the Context of Alzheimer's Disease: From Lipocrine to Memoquin and Beyond, Curr. Pharm. Des., 2009, 15, 601-613. DOI: https://doi.org/10.2174/138161209787315585

A. Petrelli, S. Giordano, From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage, Curr. Med. Chem., 2008, 15, 422-432. DOI: https://doi.org/10.2174/092986708783503212

L. Costantino, D. Barlocco, Designed Multiple Ligands: Basic Research vs Clinical Outcomes, Curr. Med. Chem., 2012, 19, 3353-3387. DOI: https://doi.org/10.2174/092986712801215883

M. Bajda, N. Guzior, M. Ignasik, B. Malawska, Multi-target-directed ligands in Alzheimer's disease treatment, Curr. Med.Chem, 2011, 18, 4949-4975. DOI: https://doi.org/10.2174/092986711797535245

J. R. Morphy, C. J. Harris, Designing Multi-Target Drugs, RCS Publishing, 2012. DOI: https://doi.org/10.1039/9781849734912

J. U. Peters, Polypharmacology in Drug Discovery, Wiley, 2012. DOI: https://doi.org/10.1002/9781118098141

L. Kupershmidt, Novel Multi-Target Therapies for Neurodegenerative Diseases Treatment, Lambert Academic Publishing, 2012.

L. Sun, C. Liang, S. Shirazian, Y. Zhou, T. Miller, J. Cui, J. Y. Fukuda, J. Y. Chu, A. Nematalla, X. Wang, H. Chen, A. Sistala, T.C. Luu, F. Tang, J. Wei, C. Tamg, Discovery of 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid(2-Diethylaminoethyl)amide, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial and Platelet-Derived Growth Factor Receptor Tyrosine Kinase, J. Med. Chem., 2003, 46, 1116-1119. DOI: https://doi.org/10.1021/jm0204183

X. H. Ma, Z. Shi, C. Tan, Y. Jiang, M. L. Go, B. C. Low, Y. Z. Chen, In-silico approaches to multi-target drug discovery: computer aided multi-target drug design, multi-target virtual screening, Pharm. Res., 2010, 27, 739-749. DOI: https://doi.org/10.1007/s11095-010-0065-2

L. Piazii, A. Rampa, A. Bisi, S. Gobbi, F. Belluti, A. Cavalli, M. Bartolini, V. Andrisano, P. Valenti, M. Racantani, 3-(4-[Benzyl(methyl)amino]methylphenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced b-amyloid aggregation: a dual function lead for Alzheimers disease therapy, J. Med. Chem., 2003, 46, 2279-2282. DOI: https://doi.org/10.1021/jm0340602

D. M. Fink, M. G. Palermo, G. M. Bores, F. P. Huger, B. E. Kurys, M. C. Merriman, G. E. Olsen, W. Petko, G. J. O'Malley, Imino 1,2,3,4-tetrahydrocyclopent[b]indolecarbamates as dual inhibitors of acetylcholinesterase and monoamine oxidase, Bioorg. Med. Chem. Lett., 1996, 6, 625-630. DOI: https://doi.org/10.1016/0960-894X(96)00072-8

M. Rosini, V. Andrisano, M. Bartolini, M. L. Bolognesi, P. Hrelia, A. Minarini, A. Tarozzi, C. Melchiorre, Rational Approach To Discover Multipotent Anti-Alzheimer Drugs, J. Med. Chem., 2005, 48, 360-363. DOI: https://doi.org/10.1021/jm049112h

H.F. Ji, H.Y. Zhang, A new strategy to combat Alzheimers disease. Combining radical-scavenging potential with metal–protein-attenuating ability in one molecule, Bioorg. Med. Chem. Lett., 2005, 15, 21-24. DOI: https://doi.org/10.1016/j.bmcl.2004.10.047

R. Pi, X. Mao, X. Chao, Z. Cheng, M. Liu, X. Duan, M. Ye, X. Chen, Z. Mei, P. Liu, W. Li, Y. Han, Tacrine-6-Ferulic Acid, a Novel Multifunctional Dimer, Inhibits Amyloid-b-Mediated Alzheimer’s Disease-Associated Pathogenesis In Vitro and In Vivo, PLoS ONE, 2012, 7, 1-8. DOI: https://doi.org/10.1371/journal.pone.0031921

O. Weinreb, S. Mandel, O. Bar-Am, M. Yogev-Falach, Y. Avramovish-Tirosh, T. Amit, M.B. Youdim, Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer's disease drugs, Neurotherapeutics, 2009, 6, 163-174. DOI: https://doi.org/10.1016/j.nurt.2008.10.030

C. Melchiorre, V. Andrisano, M. L. Bolognesi, R. Budriesi, A. Cavalii, V. Cavarini, M. Rosini, V. Tumiatti, M. Recanatini, Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer’s disease, J. Med. Chem. 1998, 41, 4186-4189. DOI: https://doi.org/10.1021/jm9810452

B. P.Guiard, M. El Mansari, P. Blier, Prospect of a dopamine contribution in the next generation of antidepressant drugs: the triple reuptake inhibitors, Curr. Drug Targets, 2009, 10, 1069-1084. DOI: https://doi.org/10.2174/138945009789735156

M. B von Neil, M. S. Beer, J. L. Castro, S. K. F. Cheng, D. C. Evans, A. Heald, L. Hitzel, P. Hunt, R. Mortishire-Smith, D. O’Connor, A.P. Watt, A. M. MacLeod, Parallel synthesis of 3-aryloxy-2-propanolamines and evaluation as dual affinity 5-htia and 5-ht re-uptake ligands, Bioorg. Med. Chem. Lett, 1999, 9, 3243-3248. DOI: https://doi.org/10.1016/S0960-894X(99)00570-3

T. Ryckmans, L. Blancon, O. Berton, C. Genicot, Y. Lamberty, B. Lallemand, P. Pasau, N. Pirlot, L. Quere, P. Talaga, First dual NK1 antagonists–serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants, Bioorg. Med. Chem. Lett, 2002, 12, 261-264. DOI: https://doi.org/10.1016/S0960-894X(01)00727-2

T. V. Lipina, V. Palomo, C. Gil, A. Martinez, J. C. Roder, Dual inhibitor of PDE7 and GSK-3eVP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice, Neuropharmacology, 2012, 30, 1-10. DOI: https://doi.org/10.1016/j.neuropharm.2012.06.032

E. Wong, F. I. Tarazi, M. Shahid, The effectiveness of multi-target agents in schizophrenia and mood disorders: relevance of receptor signature to clinical action, Pharmacol. Ther., 2010, 126, 173-185. DOI: https://doi.org/10.1016/j.pharmthera.2010.02.001

J. J. Lu, W. Pan, Y. J. Hu, T. Wang, Multi-Target Drugs: The Trend of Drug Research and Development, PLoS ONE, 2012, 7. DOI: https://doi.org/10.1371/journal.pone.0040262

S. Zhang , Y. Hu, H. Yin, Y. Wang , Drugtargets and economicvalue: an empirical study based on new drugs marketed in US during recent ten years, SciTec Man Res, 2011, 31, 172–175.

R. Morphy, Z. Rankovic, Fragments, network biology and designing multiple ligands, Drug Discov. Today, 2007, 12, 156-160. DOI: https://doi.org/10.1016/j.drudis.2006.12.006

P. Csermely, V. Agoston, S. Pongor, The efficiency of multi-target drugs: the network approach might help drug design, Trends Pharmacol. Sci., 2005, 26, 178-182. DOI: https://doi.org/10.1016/j.tips.2005.02.007

C.G. Parsons, W. Danysz, G. Quack, Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist--a review of preclinical data, Neuropharmacology, 1999, 38, 735-767. DOI: https://doi.org/10.1016/S0028-3908(99)00019-2

G. Bottegoni, A. D. Favia, M. Recanatini, A. Cavalli, The role of fragment-based and computational methods in polypharmacology, Drug Discov. Today, 2012, 17, 23-34. DOI: https://doi.org/10.1016/j.drudis.2011.08.002

B. L. Roth, D. J. Sheffler, W. K. Kroeze, Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia, Nat. Rev. Drug. Discov., 2004, 3, 353-359. DOI: https://doi.org/10.1038/nrd1346

Piotr Bojanowski

Afiliacja:

Zakład Chemii Fizycznej, Wydział Farmaceutyczny, Warszawski Uniwersytet Medyczny Poland

Piotr F. J. Lipiński

Afiliacja:

Pracownia Spektroskopii i Modelowania Molekularnego, Instytut Chemii Przemysłowej im. prof. Ignacego Mościckiego Poland

Paweł Czekała

Afiliacja:

Zakład Chemii Fizycznej, Wydział Farmaceutyczny, Warszawski Uniwersytet Medyczny Poland

Dariusz Plewczyński

Afiliacja:

Zakład Chemii Fizycznej, Wydział Farmaceutyczny, Warszawski Uniwersytet Medyczny Poland