Abstract
The case histories of five modern drugs are taken as a basis for reflection on the state of drug discovery. Two issues intimately associated with drug research are highlighted: the nature of the intellectual process leading to new discoveries; and the possibility that the principle of selective efficacy, which has guided drug research from its beginnings, might need modification, at least in some areas of pharmacotherapy.
This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
CVDHD: a cardiovascular disease herbal database for drug discovery and network pharmacology
Journal of Cheminformatics Open Access 18 December 2013
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Flower, R. J. The development of COX-2 inhibitors. Nature Rev. Drug Discov. 2, 179–191 (2003).
Rosen, G. D., Birkenmaier, T. M., Raz, A. & Holtzman, M. J. Identification of a cyclooxygenase-related gene and its potential role in prostaglandin formation. Biochem. Biophys. Res. Commun. 164, 1358–1365 (1989).
Kujubu, D. A., Fletcher, B. S., Varnuzu, B. C., Lim, R. W. & Herschmann, H. R. TISIO, a phorbol ester tumor promotor-inducible mRNA from Swiss 3T3 cells encodes a novel prostaglandin synthase/cyclooxygenase homologue. J. Biol. Chem. 266, 12866–12872 (1991).
Flower, R. J. & Vane, J. R. Selectivity of non-steroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc. Natl Acad. Sci. USA 90, 11693–11697 (1993).
Smith, W. L., DeWitt, D. L. & Garavito, R. M. Cyclooxygenases: structural and molecular biology. Am. Rev. Biochem. 69, 145–182 (2000).
FitzGerald, G. A. & Patrono, C. The coxibs, selective inhibitors of cyclooxygenase 2. N. Engl. J. Med. 345, 433–442 (2001).
Warner, T. D. & Mitchell, J. A. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 18, 790–804 (2004)
Mycek, M., Harvey, R. A. & Champe, P. Pharmacology 2nd edn, p404 (Lippincott, New York, 2000).
Vane, J. R., Bakhle Y. S. & Botting, R. M. Cyclooxygenase 1 and 2. Annu. Rev. Pharm. Toxicol. 38, 97–120 (1998).
Bombardier, C. et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N. Engl. J. Med. 343, 1520–1528 (2000).
Silverstein, F. E. et al. Gastrointestinal toxicity with celocoxib vs non-steroidal and anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284, 1247–1255 (2000).
Schnitzer, T. J. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomized controlled trial. Lancet 64, 665–674 (2004).
Solomon, S. D. et al. Adenoma Prevention with Celecoxib (APC) study investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 352, 1071–1080 (2005).
Ott, E. et al. Efficacy and safety of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib in patients undergoing coronary bypass surgery. J. Thorac. Cardiovasc. Surgery 125, 1481–1492 (2003).
An audience with... Steven Nissen. Nature Rev. Drug Discov. 5, 98 (2006).
Mitchell, J. A. & Warner, T. D. COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs. Nature Rev. Drug Discov. 5, 75–86 (2006).
Mitchell, J. A. & Evans, T. W. Cyclooxygenase-2 as a therapeutic target. Inflamm. Res. 47 (Suppl. 2), S88–S92 (1998).
Steinman, L. Blocking adhesion molecules as a therapy for multiple sclerosis: natalizumab. Nature Rev. Drug Discov. 4, 510–518 (2005).
Yednock, T. A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against the α4β1 integrin. Nature 356, 63–66 (1992).
Engelhardt, B. et al. The development of experimental autoimmune encephalomyelitis in the mouse requires α4-integrin but not α4β7-integrin. J. Clin. Invest. 102, 2096–2105 (1998).
Leger, O. J. et al. Humanization of a mouse antibody against human α4 integrin: a potential therapeutic for the treatment of multiple sclerosis. Hum. Antibodies 8, 3–16 (1997).
Miller, D. H. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348, 15–23 (2003).
Sheridan, C. Third Tysabri adverse case hits drug class. Nature Rev. Drug Discov. 4, 357–358 (2005).
Capdeville, R., Buchdunger, E., Zimmermann, J. & Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Rev. Drug Discov. 1, 493–502 (2002).
Vlahovic, G. et al. Activation of tyrosine kinases in cancer. The Oncologist 8, 531–538 (2003).
Cohen, P. Protein kinases, the major drug targets of the 21st century? Nature Rev. Drug Discov. 1, 309–316 (2002).
Melnikova, I. & Golden, J. Targeting protein kinases. Nature Rev. Drug Discov. 3, 993–994 (2004).
Ferrara, N. et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004).
Kim, K. J. et al. Inhibition for vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362, 841–844 (1993).
Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil and leukovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).
Ellis, L. M. & Kirkpatrick, P. Bevacizumab. Nature Rev. Drug Discov. 4, S8–S9 (2005).
Jain, R. K. Normalization of tumour vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).
Matthews, T. et al. Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. Nature Rev. Drug Discov. 3, 215–225 (2004).
Matthews, T. J. et al. Structural rearrangements in the transmembrane glycoprotein after receptor binding. Immunol. Rev. 140, 93–104 (1994).
Lalezari, J. P. et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N. Engl. J. Med. 348, 2175–2185 (2003).
Lazzarin, A. et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N. Engl. J. Med. 348, 2186–2195 (2003).
Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents [online], <http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL04072005001.pdf> (2005).
Horobin, D. F. Modern biomedical research: an internally self-consistent universe with little contact with medical reality? Nature Rev. Drug Discov. 2, 151–154 (2003).
Butcher, E. C. Can cell systems biology rescue drug discovery? Nature Rev. Drug Discov. 4, 461–466 (2005).
Van der Greef, J. & McBurney, R. N. Rescuing drug discovery: in vivo systems pathology and systems pharmacology. Nature Rev. Drug Discov. 4, 961–966 (2005).
Kubinyi, H. Drug research: myths, hype and reality. Nature Rev. Drug Discov. 2, 665–668 (2003).
Noseworthy, J. & Kirkpatrick, P. Natalizumab. Nature Rev. Drug Discov. 4, 101–102 (2005).
Kilby, J. M. et al. Potent suppression of HIV-1 replication by T-20, a peptide inhibitor of gp41-mediated virus entry. Nature Med. 4, 1302–1307 (1998).
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Related links
Related links
DATABASES
OMIM
Cancer.gov
Rights and permissions
About this article
Cite this article
Drews, J. Case histories, magic bullets and the state of drug discovery. Nat Rev Drug Discov 5, 635–640 (2006). https://doi.org/10.1038/nrd2084
Issue Date:
DOI: https://doi.org/10.1038/nrd2084
This article is cited by
-
Synthesis and properties of new derivatives of 4-amino-2,3-polymethylenequinolines with antioxidant function
Russian Chemical Bulletin (2023)
-
5-Amino-3-(2-aminopropyl)-1,2,4-thiadiazoles as the basis of hybrid multifunctional compounds
Russian Chemical Bulletin (2014)
-
CVDHD: a cardiovascular disease herbal database for drug discovery and network pharmacology
Journal of Cheminformatics (2013)
-
A Drug Mystery of Heterocycles: Various Molecules for One Target or One Compound for Multiple Targets?
Chemistry of Heterocyclic Compounds (2013)