生物活性

• 描述The hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, and ischemic and metabolic disease inter alia. Hypoxia-inducible factor-α (HIF-α) mediates the cells' transcriptional response to hypoxia. HIF-1α was shown to be increased in concentration in cells exposed to low oxygen and to bind to the promoter of the erythropoietin gene. HIF-1α forms a heterodimeric protein complex that includes HIF-1β and p300 and then binds to the hypoxia response element consensus sequences in the promoter region of hypoxia-responsive genes and up-regulates their expression. JNJ-42041935, was a potent, 2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes with pKi of 7.3 - 7.9. In a purified enzyme and cell-based assays, JNJ-42041935 was the most potent inhibitor of PHD2 _{181 - 417} with a pIC₅₀ value of 7.0, also inhibited full-length PHD1, PHD2, and PHD3 enzymes with pKI values of 7.91, 7.29, and 7.65, respectively. The Km values for these isotypes for 2-OG were 0.80μM, 0.50μM, and 0.82 μM, respectively. It showed that JNJ-42041935 is a potent, 2-OG-competitive, reversible, and selective inhibitor of all three PHD isozymes. JNJ-42041935 was evaluated in the HIF-driven luciferase mouse model. The result showed that two hours after oral administration of 300 μmol/kg JNJ-42041935, the bioluminescence over the peritoneal area was increased by 2.2-fold relative to luciferase-treated vehicle controls, and six hours later, JNJ-42041935 stimulated erythropoietin secretion in vivo. Furthermore, administration of JNJ-42041935 (100 μmol/kg, p.o.) for 5 consecutive days resulted in a 2-fold increase in reticulocytes, an increase in hemoglobin by 2.3 g/dl, and an increase in the hematocrit of 9%. In a all, JNJ-42041935 is a new tool compound that is potent, 2-OG-competitive, reversible, and selective inhibitor of PHD enzymes that can be used to investigate the role of this target across a range of biological systems^[2].
• 作用机制JNJ-42041935 binds to PHD2 enzyme in a 2-OG competitive mechanism of action. The acidic group present in JNJ-42041935 formed a salt bridge with Arg383. The lone pair of electrons on the nitrogen atom of the pyrazole and the benzimidizole bound to iron in the active site in a bidentate fashion. The other benzimidizole NH formed a hydrogen bond with a conserved water molecule that also participated in a hydrogen bond with Tyr303 of the protein^[2].

• 动物研究
  剂量	Mice: 300 μmol/kg[1] (p.o.)
  给药途径	p.o.