Prodrugs--from serendipity to rational design

Pharmacological Reviews
Kristiina M HuttunenJarkko Rautio

Abstract

The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term prodrug was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in de...Continue Reading

References

Jun 1, 1976·American Journal of Ophthalmology·M B KabackB Becker
Feb 1, 1979·American Journal of Ophthalmology·A N KohnS M Podos
Mar 1, 1978·Ophthalmology·A I MandellA E Kitabchi
Oct 1, 1976·Journal of Pharmaceutical Sciences·A Hussain, J E Truelove
Jan 1, 1986·Canadian Journal of Physiology and Pharmacology·J Sawynok
Jan 1, 1988·Drug Metabolism Reviews·L A Svensson, A Tunek
Jul 1, 1986·International Journal of Radiation Oncology, Biology, Physics·E M ZemanW W Lee
Sep 1, 1983·The Journal of Antimicrobial Chemotherapy·G B Elion
Jan 1, 1995·Annual Review of Pharmacology and Toxicology·George SachsS Hersey
Jan 1, 1993·Journal of Medical Virology·G Darby
Jun 1, 1996·Neurology·T R BrowneM A Eldon
Oct 1, 1996·Clinical Pharmacokinetics·D S Sitar
Oct 1, 1996·Journal of Emergency Nursing : JEN : Official Publication of the Emergency Department Nurses Association·K Bradbury-Golas, L Carson
Apr 29, 1998·European Journal of Clinical Pharmacology·K M KaukonenPertti J Neuvonen
May 20, 1998·Drugs·R H FosterP Benfield
Oct 1, 1998·Biochemical and Biophysical Research Communications·P V BalimaneP J Sinko
Sep 24, 1999·Drugs·S Noble, K L Goa
Oct 8, 1999·The American Journal of Cardiology·P J GruerJ A Tobert
Mar 22, 2001·Advanced Drug Delivery Reviews·D Hörter, J B Dressman
Mar 29, 2001·Drugs·K McClellan, Caroline M Perry
Apr 20, 2001·Journal of Medicinal Chemistry·H van De WaterbeemdD K Walker
Oct 9, 2001·American Journal of Ophthalmology·P A NetlandTravoprost Study Group
Oct 16, 2001·European Journal of Medicinal Chemistry·William A Denny
Apr 16, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tetsuo SatohBert N La Du
Sep 3, 2002·Survey of Ophthalmology·Remo SusannaYoshiaki Kitazawa
Jan 16, 2003·Journal of the American Chemical Society·Robert F AndersonWilliam A Denny
Apr 8, 2003·Current Medicinal Chemistry. Anti-cancer Agents·S PapotJ-P Gesson
Apr 30, 2003·Expert Opinion on Biological Therapy·Sridhar DuvvuriAshim K Mitra
Jun 14, 2003·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Mark R HellbergGustav Graff
Aug 27, 2003·Medicinal Research Reviews·Kenneth B Sloan, Scott C Wasdo
Aug 16, 1958·Nature·A ALBERT
Sep 23, 2003·Drugs·Toni Dando, Greg L Plosker
Sep 25, 2003·European Journal of Clinical Pharmacology·Kazuishi SekinoTatsuji Iga
Nov 1, 2003·Thrombosis Research·J R Vane, R M Botting
Apr 30, 2004·Journal of Medicinal Chemistry·Peter EttmayerBernard Testa
Jun 12, 2004·Advanced Drug Delivery Reviews·Soumyajit MajumdarAshim K Mitra
Jun 24, 2004·Journal of the American Chemical Society·Jai Moo ShinGeorge Sachs
Sep 2, 2004·The Journal of Pharmacology and Experimental Therapeutics·Mark D ErionDavid A Bullough
Oct 23, 2004·Biochemical Pharmacology·Bernard Testa
Dec 8, 2004·Current Drug Metabolism·Sridhar DuvvuriAshim K Mitra
Dec 31, 2004·The New England Journal of Medicine·Yvan GascheJules Desmeules
May 24, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Teruko ImaiMitsuru Hashimoto
Jul 21, 2005·Clinical Pharmacokinetics·Domenic A SicaSiddhartha Ghosh
Oct 27, 2005·Nucleosides, Nucleotides & Nucleic Acids·K Raja ReddyMark D Erion
Dec 27, 2005·Current Drug Targets. Immune, Endocrine and Metabolic Disorders·M E Ganapathy, V Ganapathy
Feb 21, 2006·Clinical Pharmacokinetics·Mary Beth WireScott Studenberg
Apr 7, 2006·The Journal of Pharmacology and Experimental Therapeutics·Masahiro TsudaKen-ichi Inui
Apr 28, 2006·Journal of Pharmaceutical Sciences·Bianca M Liederer, Ronald T Borchardt
Jun 9, 2006·International Journal of Pharmaceutics·Gladys E Granero, Gordon L Amidon
Jul 22, 2006·Drug Metabolism and Pharmacokinetics·Teruko Imai
Aug 22, 2006·Chemico-biological Interactions·Tetsuo Satoh, Masakiyo Hosokawa
Nov 1, 2006·Molecular Microbiology·Graham S Timmins, Vojo Deretic
Nov 17, 2006·Pharmaceutical Research·Kenneth B SloanJarkko Rautio
Feb 22, 2007·Current Drug Discovery Technologies·Jia-You Fang, Yann-Lii Leu
Mar 21, 2007·Chemistry & Biodiversity·Bernard Testa, Stefanie D Krämer
May 8, 2007·Cancer Chemotherapy and Pharmacology·Ricardo BellottJacques Robert
Jun 15, 2007·Paediatric Anaesthesia·Polina VoronovNarasimhan Jagannathan
Jul 14, 2007·Advanced Drug Delivery Reviews·Valentino J Stella, Kwame W Nti-Addae
Sep 18, 2007·International Journal of Radiation Oncology, Biology, Physics·Kevin O HicksWilliam R Wilson
Nov 17, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Stefan BlechWilly Roth
Jan 26, 2008·Nature Reviews. Drug Discovery·Jarkko RautioJouko Savolainen
Feb 28, 2008·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Tuire TirkkonenKari Laine
Mar 1, 2008·Nature Reviews. Drug Discovery·Paul D Dobson, Douglas B Kell
May 1, 2008·Drug Metabolism and Pharmacokinetics·Mariko KobayashiKazuyuki Ueno
Jul 29, 2008·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Eva M del AmoMarjo Yliperttula
Aug 12, 2008·Current Clinical Pharmacology·Soo-Peang Khor, Ann Hsu
Oct 16, 2008·Current Medicinal Chemistry·Kristiina M HuttunenJarkko Rautio
Dec 10, 2008·Critical Reviews in Therapeutic Drug Carrier Systems·Tarun GoswamiXiaoling Li
Mar 14, 2009·Journal of Industrial Microbiology & Biotechnology·Ronald Bentley
Jul 7, 2009·The American Journal of Cardiology·Evan A SteinJohn J P Kastelein
Jul 14, 2009·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Hiltrud Brauch, V Craig Jordan
Aug 21, 2009·The New England Journal of Medicine·Catherine CiszkowskiGideon Koren
Nov 26, 2009·Chemistry & Biodiversity·Christa E Müller
Dec 5, 2009·Pharmacogenomics·Navin PintoM Eileen Dolan
Jan 15, 2010·Drug Development and Industrial Pharmacy·Shahrzad MissaghiAli R Rajabi-Siahboomi
Mar 13, 2010·Future Oncology·William A Denny
May 5, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kostandinos SiderasMatthew P Goetz
May 8, 2010·Expert Opinion on Drug Metabolism & Toxicology·Bérénice GiraudAngelo Paci
May 28, 2010·Pharmacogenomics·Ulrike M StamerFrank Stüber
Jul 31, 2010·Arteriosclerosis, Thrombosis, and Vascular Biology·Wolfgang G EisertJoanne van Ryn
Sep 8, 2010·Journal of Pharmaceutical Sciences·Valentino J Stella
Oct 30, 2010·Nature Reviews. Drug Discovery·Bethan Hughes
Nov 26, 2010·Journal of Neurology·Oleh Hornykiewicz
Dec 21, 2010·Nature Medicine·Heleen J BoumanDirk Taubert

Citations

Jul 10, 2013·Journal of Molecular Modeling·Rafik KaramanSabino A Bufo
May 2, 2012·Journal of the American Chemical Society·Matthew C ParrottJoseph M DeSimone
Feb 6, 2013·Journal of the American Chemical Society·Andrew G CheethamHonggang Cui
Dec 19, 2012·International Journal of Molecular Sciences·Amjad M Qandil
Jun 10, 2014·Annual Review of Chemical and Biomolecular Engineering·I M MarruchoL P N Rebelo
Oct 27, 2012·Advanced Drug Delivery Reviews·Balvinder S VigJarkko Rautio
Oct 11, 2014·International Journal of Breast Cancer·Katie M Kern, Jennifer R Schroeder
Feb 18, 2016·Nature Chemical Biology·Jie Li, Peng R Chen
Oct 16, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Arik DahanShimon Ben-Shabat
Jan 6, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Daniela Hartmann JornadaMan Chin Chung
Jul 23, 2013·Journal of Drug Targeting·Hairui LiLifeng Kang
Jan 21, 2016·Expert Opinion on Drug Delivery·Wajd Amly, Rafik Karaman
Aug 29, 2014·Expert Opinion on Drug Discovery·Rafik Karaman
Jun 19, 2012·Expert Opinion on Drug Delivery·Arik DahanRafik Karaman
Apr 18, 2012·Expert Opinion on Drug Delivery·Jia-You Fang, Saleh A Al-Suwayeh
Jan 7, 2014·Expert Opinion on Drug Metabolism & Toxicology·Walter Emil Haefeli, Alexandra Carls
Feb 18, 2016·Journal of Pharmaceutical Sciences·Alfred C F RumondorFilippos Kesisoglou
Apr 9, 2013·Pharmacological Reports : PR·Jolanta B ZawilskaAgnieszka B Olejniczak
Sep 3, 2013·Drug Discovery Today·Sophie-Dorothee ClasRebecca Nofsinger
Dec 1, 2015·Postgraduate Medicine·Jeffrey A Gudin, Srinivas R Nalamachu
Apr 28, 2016·Clinical Pharmacology in Drug Development·Alan Wayne Jones
May 15, 2015·Journal of Medicinal Chemistry·Kevin B DanielSeth M Cohen
Aug 26, 2014·ACS Medicinal Chemistry Letters·Erin M SkodaPeter Wipf
Oct 2, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Hao SuHonggang Cui
Nov 28, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Stephen C Mitchell
Feb 16, 2016·Journal of Drug Targeting·Kevin B Ita
Mar 21, 2016·Journal of Pharmaceutical Sciences·Huixin QiHongjian Zhang
Sep 4, 2013·Chemical Biology & Drug Design·Rafik Karaman
Jul 6, 2014·Pharmacotherapy·Shawn FlanaganPhilippe G Prokocimer
Nov 19, 2015·Pharmaceutical Patent Analyst·Rosa FormicolaMariangela Sodano
Dec 29, 2013·International Journal of Pharmaceutics·Min-Ho ParkCheong-Weon Cho
Mar 22, 2015·Biotechnology Advances·Luis E IglesiasAdolfo M Iribarren
Apr 25, 2015·Nature Reviews. Drug Discovery·Johannes KirchmairGisbert Schneider
May 1, 2015·Daru : Journal of Faculty of Pharmacy, Tehran University of Medical Sciences·Bibi Marjan Razavi, Hossein Hosseinzadeh
Apr 23, 2016·Advanced Drug Delivery Reviews·Huaimin WangBing Xu
Dec 3, 2014·Trends in Pharmacological Sciences·Cong LuoZhonggui He
Oct 8, 2014·Cellular and Molecular Life Sciences : CMLS·Lisa SandersjööJohn Löfblom
Mar 10, 2015·Metabolomics : Official Journal of the Metabolomic Society·Steve O HaganDouglas B Kell
Aug 12, 2014·Frontiers in Pharmacology·Anne Mai WassermannDouglas S Auld
Jul 28, 2016·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Wen LiZhe-Sheng Chen
Jun 4, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Soraya da Silva SantosJeanine Giarolla
Jul 2, 2016·Journal of Medicinal Chemistry·Uttio Roy ChowdhuryPeter I Dosa
Jul 17, 2016·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Vikas KumarRam A Vishwakarma
Sep 16, 2014·The Journal of Physical Chemistry. B·Oraphan PhuangsawaiM Paul Gleeson
Jan 12, 2012·ACS Medicinal Chemistry Letters·Vincent GasparikNelly Frossard
Aug 14, 2013·Molecular Pharmaceutics·Mamta Kapoor, Ronald A Siegel
Jun 6, 2014·ACS Medicinal Chemistry Letters·Giulia VignaroliMaurizio Botta
Jun 6, 2014·ACS Medicinal Chemistry Letters·Wataru HakamataToshiyuki Nishio
Sep 28, 2013·Biochemistry·Ronak Tilvawala, R F Pratt
Sep 22, 2016·Journal of Cheminformatics·Ola SpjuthNina Jeliazkova
Sep 22, 2016·Drug Discovery Today·Giorgia MoriMaria Rosalia Pasca
Dec 3, 2016·Nature Reviews. Drug Discovery·Rita SantosJohn P Overington
Dec 18, 2016·Protein Engineering, Design & Selection : PEDS·Nirav Y ShelatMarc Ostermeier
Jan 28, 2017·Expert Opinion on Drug Delivery·Benson J EdagwaHoward E Gendelman
Mar 24, 2017·Chemical Research in Toxicology·John E Casida
Apr 11, 2017·Drug Metabolism Reviews·Ivanna HrynchakVera Marisa Costa
Dec 30, 2014·Chemical Science·Nicholas A McGrathRonald T Raines
Mar 3, 2017·Journal of Medicinal Chemistry·Ewgenij ProschakDaniel Merk
Mar 14, 2017·Bioorganic & Medicinal Chemistry Letters·Yoshio Hamada
Dec 29, 2016·Bioorganic & Medicinal Chemistry Letters·Miguel Flores-RamosRafael Castillo
Mar 27, 2015·Chemical Communications : Chem Comm·Christian PerezSeth M Cohen
Sep 26, 2017·Angewandte Chemie·Richard J D HatleyPauline T Lukey
Nov 11, 2017·Applied Biochemistry and Biotechnology·Rina D Koyani, Rafael Vazquez-Duhalt
Apr 28, 2018·Nature Reviews. Drug Discovery·Jarkko RautioMichael J Hageman
May 31, 2016·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Chunqiu ZhangXing-Jie Liang
Aug 6, 2016·Dalton Transactions : an International Journal of Inorganic Chemistry·Uttara BasuShanta Dhar
Jul 12, 2018·Chemical Communications : Chem Comm·Zhiyi LinBenson J Edagwa
Sep 6, 2017·Archiv der Pharmazie·Daniela R OliveiraJoão P S Fernandes
Sep 21, 2018·Organic & Biomolecular Chemistry·Ming-Sheng XieHai-Ming Guo
Oct 3, 2018·Therapeutic Delivery·Nikhitha K ShanmukhanSamuel Gideon
Mar 2, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Yuantao HuoShelli Renee McAlpine
Feb 23, 2013·Organic & Biomolecular Chemistry·Jun WuXiang Zhou
May 2, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Murali SubramanianSandhya Mandlekar
Aug 16, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tomoko IshizukaTakashi Izumi
Nov 30, 2019·Natural Product Research·Shravankumar Kankala, Ravinder Vadde
Oct 10, 2019·Mini Reviews in Medicinal Chemistry·Alexey V DobrydnevMaria V Popova
Jun 5, 2013·Drug Metabolism and Drug Interactions·Dayanidhi BeheraGirish S Gudi
May 24, 2020·International Journal of Molecular Sciences·Milica MarkovicArik Dahan
Jul 2, 2020·Medicina·Emilia BłeszyńskaMarcin Renke
Jan 21, 2017·Advanced Science·Gurusamy SaravanakumarWon Jong Kim
Sep 29, 2018·ChemCatChem·Flóra NagyLászló Poppe
Sep 21, 2019·Future Medicinal Chemistry·Ming-Hsien LinJia-You Fang
Jan 15, 2020·The Journal of Antibiotics·Sergey D NegryaLiudmila A Alexandrova
Apr 29, 2020·Nature Materials·Tanmay A KulkarniHoward E Gendelman
Oct 11, 2014·Chemistry : a European Journal·Song DingUlrich Bierbach
Sep 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nuno ValeMaria João Gouveia
May 2, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Srishti SinghRobert McKenna
Feb 6, 2017·Clinical Science·Lea Gaignebet, Georgios Kararigas
Oct 22, 2019·Future Medicinal Chemistry·Arik DahanShimon Ben-Shabat
Jan 7, 2019·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Jing LiAiguo Hu
Aug 10, 2013·ChemMedChem·Christian PerezSeth M Cohen
Nov 29, 2012·Organic & Biomolecular Chemistry·Jun WuXiang Zhou
Sep 28, 2017·Bioengineering·Miguel Gisbert-GarzaránMaría Vallet-Regí
Aug 14, 2018·Expert Opinion on Drug Discovery·Xin-Yu Zhang, Adnan A Elfarra
Oct 16, 2018·Medicinal Research Reviews·Milica MarkovicArik Dahan
Jan 6, 2019·AAPS PharmSciTech·Tushar DateSanyog Jain
May 31, 2019·Expert Opinion on Drug Metabolism & Toxicology·Yanfeng WangRichard S Geary
May 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Izabela Muszalska-KolosAgnieszka Klupczyńska
May 7, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jack L SloanePaul A Wender
Sep 3, 2020·Chemistry : a European Journal·Laura K BucktonShelli Renee McAlpine
Dec 4, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yayue WangPing Feng
Jun 2, 2020·Advanced Drug Delivery Reviews·D J BraydenR J Mrsny
Sep 3, 2020·Computers in Biology and Medicine·Himanshu Verma, Om Silakari
Feb 11, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Johannes KargesSeth M Cohen
Jan 20, 2021·Chemistry : a European Journal·Javid Ahmad MallaPinaki Talukdar
Feb 15, 2021·Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy·Urszula Śliwińska-Hill
Nov 17, 2020·Frontiers in Genetics·Ping Siu KeeSimran D S Maggo
Nov 7, 2020·International Journal of Molecular Sciences·Rahul PatelAmr ElShaer
Mar 16, 2021·AAPS PharmSciTech·Olivia L LanierAnuj Chauhan
Aug 22, 2020·ACS Pharmacology & Translational Science·Andrew J Wiemer
Jul 30, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Nadia FattahiHélder A Santos
Feb 9, 2018·Bioorganic Chemistry·Valeria RomanucciArmando Zarrelli
Feb 28, 2018·International Journal of Biological Macromolecules·Muhammad AminKevin J Edgar

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