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New era for drug discovery and development in renal disease

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Miyata, Toshio Kikuchi, Katsushi Kiyomoto, Hideyasu Van Ypersele de Strihou, Charles [UCL]

Drug discovery and development is a lengthy and expensive process. Testing new agents in humans at an early stage could reduce the time and costs involved in identifying drugs that are likely to succeed in clinical studies. New guidance has outlined the concept of exploratory clinical trials, which provide important information on a drug's distribution as well as its physiological and pharmacological effects in humans. This strategy reduces the need for preclinical testing by limiting the dose and duration of exposure to a new drug in humans to below those required by the traditional testing of investigational new drugs. Exploratory, first-in-man studies should provide insights into human physiology and pharmacology, identify therapeutic targets relevant to disease and increase our knowledge of a drug's characteristics. Implementation of a new drug also requires the development of useful biomarkers of disease and of the drug's efficacy, as well as sensitive molecular imaging techniques. In this Review, we outline the benefits of exploratory clinical trials, especially in academia, and provide an overview of the experimental tools necessary for rational drug discovery and development.

Document type Article de périodique (Journal article) – Synthèse de littérature – Journal Article, Review
Access type Accès restreint
Publication date 2011
Language Anglais
Journal information "Nature Reviews Nephrology" - Vol. 7, no. 8, p. 469-477 (2011)
Peer reviewed yes
Publisher Nature Publishing Group ((United Kingdom) London)
issn 1759-5061
e-issn 1759-507X
Publication status Publié
Affiliations UCL - SSS/IREC/NEFR - Pôle de Néphrologie
UCL - (SLuc) Service de néphrologie
MESH Subject Chemistry, Pharmaceutical ; Clinical Trials as Topic ; Drug Design ; Drug Evaluation ; Drug Evaluation, Preclinical ; Drugs, Investigational ; Humans ; Kidney Diseases - drug therapy ; Pharmacogenetics
Links
  1. Ashburn Ted T., Thor Karl B., Drug repositioning: identifying and developing new uses for existing drugs, 10.1038/nrd1468
  2. Reichert Janice M., A guide to drug discovery: Trends in development and approval times for new therapeutics in the United States, 10.1038/nrd1178
  3. Levey A.S., Atkins R., Coresh J., Cohen E.P., Collins A.J., Eckardt K.-U., Nahas M.E., Jaber B.L., Jadoul M., Levin A., Powe N.R., Rossert J., Wheeler D.C., Lameire N., Eknoyan G., Chronic kidney disease as a global public health problem: Approaches and initiatives – a position statement from Kidney Disease Improving Global Outcomes, 10.1038/sj.ki.5002343
  4. Boyd R A, Lalonde R L, Nontraditional approaches to first-in-human studies to increase efficiency of drug development: will microdose studies make a significant impact?, 10.1038/sj.clpt.6100058
  5. Kola Ismail, Landis John, Opinion: Can the pharmaceutical industry reduce attrition rates?, 10.1038/nrd1470
  6. Karara Adel H., Edeki Timi, McLeod James, Tonelli Alfred P., Wagner John A., PhRMA Survey on the Conduct of First-in-Human Clinical Trials Under Exploratory Investigational New Drug Applications, 10.1177/0091270009344987
  7. Sugiyama Yuichi, Yamashita Shinji, Impact of microdosing clinical study — Why necessary and how useful?, 10.1016/j.addr.2010.09.010
  8. LAPPIN G, KUHNZ W, JOCHEMSEN R, KNEER J, CHAUDHARY A, OOSTERHUIS B, DRIJFHOUT W, ROWLAND M, GARNER R, Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs, 10.1016/j.clpt.2006.05.008
  9. Hajduk Philip J., Greer Jonathan, A decade of fragment-based drug design: strategic advances and lessons learned, 10.1038/nrd2220
  10. Meagher Kristin L., Carlson Heather A., Incorporating Protein Flexibility in Structure-Based Drug Discovery:  Using HIV-1 Protease as a Test Case, 10.1021/ja0469378
  11. Chessari Gianni, Woodhead Andrew J., From fragment to clinical candidate—a historical perspective, 10.1016/j.drudis.2009.04.007
  12. Ekins S, Mestres J, Testa B, In silicopharmacology for drug discovery: applications to targets and beyond, 10.1038/sj.bjp.0707306
  13. Ha Hunjoo, Oh Eun Y., Lee Hi B., The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases, 10.1038/nrneph.2009.15
  14. Rondeau E., Clin. Nephrol., 33, 55 (1990)
  15. Nakamura T., J. Am. Soc. Nephrol., 7, 2434 (1996)
  16. Hamano Kazumasa, Iwano Masayuki, Akai Yasuhiro, Sato Hiroaki, Kubo Atsushi, Nishitani Yoshiharu, Uyama Hideto, Yoshida Yukiko, Miyazaki Masanobu, Shiiki Hideo, Kohno Shigeru, Dohi Kazuhiro, Expression of glomerular plasminogen activator inhibitor type 1 in glomerulonephritis, 10.1053/ajkd.2002.31986
  17. Matsuo Shunya, Lepez-Guisa JeseS M., Cai Xiaohe, Okamura Daryl M., Alpers Charles E., Bumgarner Roger E., Peters Mette A., Zhang Guoqiang, Eddy Allison A., Multifunctionality of PAI-1 in fibrogenesis: Evidence from obstructive nephropathy in PAI-1–overexpressing mice, 10.1111/j.1523-1755.2005.00327.x
  18. Kitching A. R., Plasminogen Activator Inhibitor-1 Is a Significant Determinant of Renal Injury in Experimental Crescentic Glomerulonephritis, 10.1097/01.asn.0000065550.13931.00
  19. Nicholas Susanne B., Aguiniga Elsa, Ren Yuelan, Kim Jason, Wong Joyce, Govindarajan Nalini, Noda Masakuni, Wang Wei, Kawano Yasuko, Collins Alan, Hsueh Willa A., Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy, 10.1111/j.1523-1755.2005.00207.x
  20. Huang Yufeng, Haraguchi Masashi, Lawrence Daniel A., Border Wayne A., Yu Ling, Noble Nancy A., A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis, 10.1172/jci200318038
  21. Izuhara Y., Takahashi S., Nangaku M., Takizawa S., Ishida H., Kurokawa K., van Ypersele de Strihou C., Hirayama N., Miyata T., Inhibition of Plasminogen Activator Inhibitor-1: Its Mechanism and Effectiveness on Coagulation and Fibrosis, 10.1161/atvbaha.107.157479
  22. Goto Junichi, Kataoka Ryoichi, Hirayama Noriaki, Ph4Dock:  Pharmacophore-Based Protein−Ligand Docking, 10.1021/jm0493818
  23. Izuhara Yuko, Yamaoka Nagahisa, Kodama Hidehiko, Dan Takashi, Takizawa Shunya, Hirayama Noriaki, Meguro Kanji, van Ypersele de Strihou Charles, Miyata Toshio, A Novel Inhibitor of Plasminogen Activator Inhibitor-1 Provides Antithrombotic Benefits Devoid of Bleeding Effect in Nonhuman Primates, 10.1038/jcbfm.2009.272
  24. Miyata Toshio, van Ypersele de Strihou Charles, Diabetic nephropathy: a disorder of oxygen metabolism?, 10.1038/nrneph.2009.211
  25. Fine L. G., Kidney Int. Suppl., 65, S74 (1998)
  26. Semenza Gregg L., Targeting HIF-1 for cancer therapy, 10.1038/nrc1187
  27. Marx J., CELL BIOLOGY: How Cells Endure Low Oxygen, 10.1126/science.303.5663.1454
  28. Epstein Andrew C.R., Gleadle Jonathan M., McNeill Luke A., Hewitson Kirsty S., O'Rourke John, Mole David R., Mukherji Mridul, Metzen Eric, Wilson Michael I., Dhanda Anu, Tian Ya-Min, Masson Norma, Hamilton Donald L., Jaakkola Panu, Barstead Robert, Hodgkin Jonathan, Maxwell Patrick H., Pugh Christopher W., Schofield Christopher J., Ratcliffe Peter J., C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation, 10.1016/s0092-8674(01)00507-4
  29. Schofield Christopher J., Ratcliffe Peter J., Oxygen sensing by HIF hydroxylases, 10.1038/nrm1366
  30. Nangaku M., Izuhara Y., Takizawa S., Yamashita T., Fujii-Kuriyama Y., Ohneda O., Yamamoto M., van Ypersele de Strihou C., Hirayama N., Miyata T., A Novel Class of Prolyl Hydroxylase Inhibitors Induces Angiogenesis and Exerts Organ Protection Against Ischemia, 10.1161/atvbaha.107.148551
  31. Fong G-H, Takeda K, Role and regulation of prolyl hydroxylase domain proteins, 10.1038/cdd.2008.10
  32. Takeda K., Cowan A., Fong G.-H., Essential Role for Prolyl Hydroxylase Domain Protein 2 in Oxygen Homeostasis of the Adult Vascular System, 10.1161/circulationaha.107.701516
  33. Takeda K., Aguila H. L., Parikh N. S., Li X., Lamothe K., Duan L.-J., Takeda H., Lee F. S., Fong G.-H., Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins, 10.1182/blood-2007-09-114561
  34. Aragonés Julián, Schneider Martin, Van Geyte Katie, Fraisl Peter, Dresselaers Tom, Mazzone Massimiliano, Dirkx Ruud, Zacchigna Serena, Lemieux Hélène, Jeoung Nam Ho, Lambrechts Diether, Bishop Tammie, Lafuste Peggy, Diez-Juan Antonio, Harten Sarah K, Van Noten Pieter, De Bock Katrien, Willam Carsten, Tjwa Marc, Grosfeld Alexandra, Navet Rachel, Moons Lieve, Vandendriessche Thierry, Deroose Christophe, Wijeyekoon Bhathiya, Nuyts Johan, Jordan Benedicte, Silasi-Mansat Robert, Lupu Florea, Dewerchin Mieke, Pugh Chris, Salmon Phil, Mortelmans Luc, Gallez Bernard, Gorus Frans, Buyse Johan, Sluse Francis, Harris Robert A, Gnaiger Erich, Hespel Peter, Van Hecke Paul, Schuit Frans, Van Veldhoven Paul, Ratcliffe Peter, Baes Myriam, Maxwell Patrick, Carmeliet Peter, Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism, 10.1038/ng.2007.62
  35. Watanabe Daisuke, Suzuma Kiyoshi, Matsui Shigeyuki, Kurimoto Masafumi, Kiryu Junichi, Kita Mihori, Suzuma Izumi, Ohashi Hirokazu, Ojima Tomonari, Murakami Tomoaki, Kobayashi Toshihiro, Masuda Seiji, Nagao Masaya, Yoshimura Nagahisa, Takagi Hitoshi, Erythropoietin as a Retinal Angiogenic Factor in Proliferative Diabetic Retinopathy, 10.1056/nejmoa041773
  36. Shah S. V., Baliga R., Rajapurkar M., Fonseca V. A., Oxidants in Chronic Kidney Disease, 10.1681/asn.2006050500
  37. Forbes J. M., Coughlan M. T., Cooper M. E., Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes, 10.2337/db08-0057
  38. Shuaib Ashfaq, Lees Kennedy R., Lyden Patrick, Grotta James, Davalos Antonio, Davis Stephen M., Diener Hans-Christoph, Ashwood Tim, Wasiewski Warren W., Emeribe Ugochi, NXY-059 for the Treatment of Acute Ischemic Stroke, 10.1056/nejmoa070240
  39. Bath PMW, Gray LJ, Bath AJG, Buchan A, Miyata T, Green AR, Effects of NXY-059 in experimental stroke: an individual animal meta-analysis, 10.1111/j.1476-5381.2009.00196.x
  40. Nguyen Truyen, Sherratt Philip J., Pickett Cecil B., REGULATORY MECHANISMS CONTROLLING GENE EXPRESSION MEDIATED BY THE ANTIOXIDANT RESPONSE ELEMENT, 10.1146/annurev.pharmtox.43.100901.140229
  41. Kobayashi Makoto, Yamamoto Masayuki, Molecular Mechanisms Activating the Nrf2-Keap1 Pathway of Antioxidant Gene Regulation, 10.1089/ars.2005.7.385
  42. Leonard M. O., Kieran N. E., Howell K., Burne M. J., Varadarajan R., Dhakshinamoorthy S., Porter A. G., O'Farrelly C., Rabb H., Taylor C. T., Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury, 10.1096/fj.06-5097fje
  43. Liu Manchang, Grigoryev Dmitry N., Crow Michael T., Haas Mark, Yamamoto Masayuki, Reddy Sekhar P., Rabb Hamid, Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice, 10.1038/ki.2009.157
  44. Yoh K., Genes Cells, 13, 1159 (2008)
  45. Cho Hye-Youn, Jedlicka Anne E., Reddy Sekhar P. M., Kensler Thomas W., Yamamoto Masayuki, Zhang Liu-Yi, Kleeberger Steven R., Role of NRF2 in Protection Against Hyperoxic Lung Injury in Mice, 10.1165/ajrcmb.26.2.4501
  46. Cho H. Y., FASEB J., 18, 1258 (2004)
  47. Shih A. Y., A Small-Molecule-Inducible Nrf2-Mediated Antioxidant Response Provides Effective Prophylaxis against Cerebral Ischemia In Vivo, 10.1523/jneurosci.4014-05.2005
  48. Itoh K., Wakabayashi N., Katoh Y., Ishii T., Igarashi K., Engel J. D., Yamamoto M., Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain, 10.1101/gad.13.1.76
  49. Wakabayashi Nobunao, Itoh Ken, Wakabayashi Junko, Motohashi Hozumi, Noda Shuhei, Takahashi Satoru, Imakado Sumihisa, Kotsuji Tomoe, Otsuka Fujio, Roop Dennis R, Harada Takanori, Engel James Douglas, Yamamoto Masayuki, Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation, 10.1038/ng1248
  50. Okada Kosuke, Shoda Junichi, Taguchi Keiko, Maher Jonathan M., Ishizaki Kaoru, Inoue Yoshimi, Ohtsuki Makio, Goto Nobuharu, Sugimoto Hirokazu, Utsunomiya Hirotoshi, Oda Koji, Warabi Eiji, Ishii Tetsuro, Yamamoto Masayuki, Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems, 10.1016/j.bbrc.2009.08.156
  51. Tong Kit I., Kobayashi Akira, Katsuoka Fumiki, Yamamoto Masayuki, Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism, 10.1515/bc.2006.164
  52. Hoffman John M., Gambhir Sanjiv S., Kelloff Gary J., Regulatory and Reimbursement Challenges for Molecular Imaging, 10.1148/radiol.2453060737
  53. Takasawa M., J. Cereb. Blood Flow Metab., 27, 679 (2007)
  54. Kaneta Tomohiro, Takai Yoshihiro, Iwata Ren, Hakamatsuka Takashi, Yasuda Hiroyasu, Nakayama Katsutoshi, Ishikawa Yoichi, Watanuki Shoichi, Furumoto Shozo, Funaki Yoshihito, Nakata Eiko, Jingu Keiichi, Tsujitani Michihiko, Ito Masatoshi, Fukuda Hiroshi, Takahashi Shoki, Yamada Shogo, Initial evaluation of dynamic human imaging using18F-FRP170 as a new PET tracer for imaging hypoxia, 10.1007/bf03033987
  55. Kaneta T., J. Nucl. Med., 43, 109 (2002)
  56. Rosenberger C., Khamaisi M., Abassi Z., Shilo V., Weksler-Zangen S., Goldfarb M., Shina A., Zibertrest F., Eckardt K.-U., Rosen S., Heyman S.N., Adaptation to hypoxia in the diabetic rat kidney, 10.1038/sj.ki.5002567
  57. Izuhara Y., Renoprotective Properties of Angiotensin Receptor Blockers beyond Blood Pressure Lowering, 10.1681/asn.2005050522
  58. Dieterle F., Curr. Opin. Drug Discov. Devel., 11, 60 (2008)
  59. Goodsaid F M, Blank M, Dieterle F, Harlow P, Hausner E, Sistare F, Thompson A, Vonderscher J, Novel Biomarkers of Acute Kidney Toxicity, 10.1038/clpt.2009.149
  60. Kimmelman Jonathan, Ethics at Phase 0: Clarifying the Issues, 10.1111/j.1748-720x.2007.00194.x
  61. Braun M. M., Nat. Rev. Drug Discov., 9, 519 (2010)
Bibliographic reference Miyata, Toshio ; Kikuchi, Katsushi ; Kiyomoto, Hideyasu ; Van Ypersele de Strihou, Charles. New era for drug discovery and development in renal disease. In: Nature Reviews Nephrology, Vol. 7, no. 8, p. 469-477 (2011)
Permanent URL http://hdl.handle.net/2078.1/113371