title: Prolyl hydroxylase inhibition corrects functional iron deficiency and inflammation-induced anaemia in rats.
abstract: OBJECTIVE
  Small-molecule inhibitors of prolyl hydroxylase (PHD) enzymes are a novel target for the treatment of anaemia and functional iron deficiency (FID). Other than being orally bioavailable, the differentiation of PHD inhibitors from recombinant human erythropoietin (rhEPO) has not been demonstrated.
  
  
  METHODS
  JNJ-42905343 was identified and characterized as a novel inhibitor of PHD and its action was compared with rhEPO in healthy rats and in a rat model of inflammation-induced anaemia and FID [peptidoglycan-polysaccharide (PGPS) model].
  
  
  RESULTS
  Oral administration of JNJ-42905343 to healthy rats increased the gene expression of cytochrome b (DcytB) and divalent metal-ion transporter 1 (DMT1) in the duodenum, and increased plasma EPO. Repeated administration of JNJ-42905343 for 28 days increased blood haemoglobin, mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV). The serum iron concentration was increased with low doses (0.3 mg·kg(-1) ) but reduced at high doses (6 mg·kg(-1) ). In PGPS-treated rats, administration of JNJ-42905343 for 28 days corrected FID and anaemia, as reflected by increased blood haemoglobin, MCH and MCV. Increased expression of DcytB and DMT1 genes in the duodenum resulting in increased iron availability was defined as the mechanism for these effects. rhEPO did not affect DcytB and DMT1 and was not effective in PGPS-treated rats.
  
  
  CONCLUSIONS
  PHD inhibition has a beneficial effect on iron metabolism in addition to stimulating the release of EPO. Small-molecule inhibitors of PHD such as JNJ-42905343 represent a mechanism distinct from rhEPO to treat anaemia and FID.
authors.affiliation: Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Terrance D
authors.initials: TD
authors.lastname: Barrett
authors.affiliation: School of Medicine, University of California at San Diego, San Diego, CA, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Palomino
authors.affiliation: Covenant Care, Palo Alto, CA, USA.
authors.forename: Theresa I
authors.initials: TI
authors.lastname: Brondstetter
authors.affiliation: Office of Foods and Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD, USA.
authors.forename: Kimon C
authors.initials: KC
authors.lastname: Kanelakis
authors.affiliation: Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Arcturus Therapeutics, San Diego, CA, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Yan
authors.affiliation: Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Merton
authors.affiliation: Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Freddy
authors.initials: F
authors.lastname: Schoetens
authors.affiliation: Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Jing Ying
authors.initials: JY
authors.lastname: Ma
authors.affiliation: Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Skaptason
authors.affiliation: Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Jingjin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Da-Thao
authors.initials: DT
authors.lastname: Tran
authors.affiliation: Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Venkatesan
authors.affiliation: Aetheria Therapeutics, San Diego, CA, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Rosen
authors.affiliation: Higher Todsworthy Farm, Cornwall, UK.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Shankley
authors.affiliation: Aetheria Therapeutics, San Diego, CA, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Rabinowitz
mesh_terms: D000740:Anemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics; D045303:Cytochromes b / Q000235:genetics; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D004909:Erythrocyte Indices / Q000187:drug effects; D004921:Erythropoietin / Q000097:blood / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006454:Hemoglobins / Q000032:analysis; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D010457:Peptidoglycan; D064800:Prolyl-Hydroxylase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D052999:Quinazolinones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011917:Rats, Inbred Lew; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D045303:Cytochromes b; D004921:Erythropoietin; D006454:Hemoglobins; D007501:Iron; D010457:Peptidoglycan; D064800:Prolyl-Hydroxylase Inhibitors; D011720:Pyrazoles; D052999:Quinazolinones; D000099236:Solute Carrier Family 11, Member 2; C000607368:JNJ-42905343