PMID- 35675755
OWN - NLM
STAT- MEDLINE
DCOM- 20220623
LR  - 20230807
IS  - 1768-3254 (Electronic)
IS  - 0223-5234 (Linking)
VI  - 238
DP  - 2022 Aug 5
TI  - Tetrahydropyridin-4-ylpicolinoylglycines as novel and orally active prolyl 
      hydroxylase 2 (PHD2) inhibitors for the treatment of renal anemia.
PG  - 114479
LID - S0223-5234(22)00381-6 [pii]
LID - 10.1016/j.ejmech.2022.114479 [doi]
AB  - Prolyl hydroxylase 2 (PHD2) is a key regulatory enzyme responsible for the 
      degradation of hypoxia-inducible factor-alpha (HIF-alpha). Pharmacological inhibition of 
      PHD2 stabilizes HIF-alpha and induces the production of endogenous erythropoietin 
      (EPO), which is regarded as a promising strategy for the treatment of renal 
      anemia. To date, a series of PHD2 inhibitors have been approved or advanced into 
      clinical studies. In this study, we developed a new type of PHD2 inhibitors with 
      the tetrahydropyridin-4-ylpicolinoylglycine scaffold by using a scaffold hopping 
      strategy. Among them, compound 25 showed potent inhibition toward PHD2 with an 
      IC(50) of 6.55 +/- 0.41 nM. Furthermore, compound 25 upregulated reticulocytes in 
      C57BL/6 mice. The subacute toxicological assay demonstrated 25 has no obvious 
      toxicity in vivo. Overall, compound 25 is a promising candidate for the treatment 
      of renal anemia.
CI  - Copyright (c) 2022 Elsevier Masson SAS. All rights reserved.
FAU - Su, Kaijun
AU  - Su K
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, and Department of 
      Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
FAU - Li, Zhihong
AU  - Li Z
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, and Department of 
      Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
FAU - Zhang, Linjian
AU  - Zhang L
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, and Department of 
      Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
FAU - Fang, Shaocong
AU  - Fang S
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, and Department of 
      Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
FAU - Mao, Mingxuan
AU  - Mao M
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, and Department of 
      Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
FAU - Sun, Zhuoli
AU  - Sun Z
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, and Department of 
      Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
FAU - Zhang, Xiaojin
AU  - Zhang X
AD  - Jiangsu Key Laboratory of Drug Design and Optimization, and Department of 
      Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic 
      address: zxj@cpu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20220525
PL  - France
TA  - Eur J Med Chem
JT  - European journal of medicinal chemistry
JID - 0420510
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Prolyl-Hydroxylase Inhibitors)
RN  - 0 (Pyridines)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - EC 1.14.11.29 (Egln1 protein, mouse)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
SB  - IM
EIN - Eur J Med Chem. 2023 Nov 5;259:115692. PMID: 37550158
MH  - *Anemia/drug therapy/metabolism
MH  - Animals
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - *Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & 
      inhibitors/metabolism
MH  - *Kidney Diseases/drug therapy/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Procollagen-Proline Dioxygenase/metabolism
MH  - *Prolyl-Hydroxylase Inhibitors/pharmacology
MH  - *Pyridines/pharmacology
OTO - NOTNLM
OT  - HIF
OT  - PHD2 inhibitor
OT  - Renal anemia
EDAT- 2022/06/09 06:00
MHDA- 2022/06/24 06:00
CRDT- 2022/06/08 18:17
PHST- 2022/04/07 00:00 [received]
PHST- 2022/05/15 00:00 [revised]
PHST- 2022/05/16 00:00 [accepted]
PHST- 2022/06/09 06:00 [pubmed]
PHST- 2022/06/24 06:00 [medline]
PHST- 2022/06/08 18:17 [entrez]
AID - S0223-5234(22)00381-6 [pii]
AID - 10.1016/j.ejmech.2022.114479 [doi]
PST - ppublish
SO  - Eur J Med Chem. 2022 Aug 5;238:114479. doi: 10.1016/j.ejmech.2022.114479. Epub 
      2022 May 25.