title: Structure-based drug design for hypoxia-inducible factor prolyl-hydroxylase inhibitors and its therapeutic potential for the treatment of erythropoiesis-stimulating agent-resistant anemia: raising expectations for exploratory clinical trials.
abstract: BACKGROUND
  Anemia occurs in various chronic diseases and its treatment is dramatically improved after the appearance of erythropoiesis-stimulating agents (ESA). However, there are several problems regarding the use of ESA including: i) invasiveness, ii) high cost and iii) ESA resistance. Therefore, there is a need to develop small molecule drugs which can improve these problems. Hypoxia-inducible factor (HIF) plays a key role in regulating erythropoietin production. HIF stabilizers, particularly, prolyl hydroxylase domain-containing protein (PHD) inhibitors, have emerged as small molecule-based anti-anemia medicine.
  
  
  METHODS
  This article discusses the current status of PHD inhibitors and the pros and cons of currently tested methods. Specifically, the article reviews the advantages of structure-based drug design in the development of PHD inhibitors and looks at future perspectives within the field.
  
  
  CONCLUSIONS
  Despite the fact that structure-based drug design has dramatically improved drug discovery, testing on humans is still one of the most time-consuming parts of drug discovery and one that is not accelerated by structural approaches. Exploratory clinical trials, first-in-man studies have emerged as a new strategy for preclinical and clinical development of drugs. Exploratory clinical trials will not only reduce the time and cost in preclinical trials but also provide important information on candidate drug's pharmacological effects in humans. Exploratory clinical trials may be a potential alternative strategy for the drug discovery in the future.
authors: The University of Tokyo School of Medicine, Division of Nephrology and Endocrinology, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Yoshiki
authors: Y
authors: Higashijima
authors: Tetsuhiro
authors: T
authors: Tanaka
authors: Masaomi
authors: M
authors: Nangaku
mesh_terms: D000740:Anemia / Q000188:drug therapy; D000818:Animals; D015195:Drug Design; D004351:Drug Resistance; D006397:Hematinics / Q000627:therapeutic use; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064800:Prolyl-Hydroxylase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D006397:Hematinics; D064800:Prolyl-Hydroxylase Inhibitors; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases