PMID- 35985255
OWN - NLM
STAT- MEDLINE
DCOM- 20220920
LR  - 20220920
IS  - 1768-3254 (Electronic)
IS  - 0223-5234 (Linking)
VI  - 242
DP  - 2022 Nov 15
TI  - Discovery of novel PDE4 inhibitors targeting the M-pocket from natural 
      mangostanin with improved safety for the treatment of Inflammatory Bowel 
      Diseases.
PG  - 114631
LID - S0223-5234(22)00533-5 [pii]
LID - 10.1016/j.ejmech.2022.114631 [doi]
AB  - Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative 
      intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors 
      were reported to be novel anti-IBD agents, but their clinical use was hampered by 
      side effects such as emesis and nausea. Herein, structure-based discovery of 
      natural mangostanin (1) targeting the M-pocket resulted in the novel and potent 
      PDE4 inhibitor 22d (IC(50) = 3.5 nM) and favorable physico-chemical properties. 
      X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained 
      the key interactions between PDE4 and roflumilast. Worthy to note that compounds 
      22d and our previously reported 4e and 18a, originating from mangostanin, all 
      caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the 
      safety superiority of scaffold in mangostanin derivatives over that in positive 
      roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited 
      comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, 
      twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, 
      indicating its potential as a novel anti-IBD agent.
CI  - Copyright (c) 2022 Elsevier Masson SAS. All rights reserved.
FAU - Liu, Haobai
AU  - Liu H
AD  - School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 
      Guangzhou, 510006, PR China.
FAU - Wang, Quan
AU  - Wang Q
AD  - School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, PR 
      China.
FAU - Huang, Yue
AU  - Huang Y
AD  - School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, PR 
      China.
FAU - Deng, Jinhui
AU  - Deng J
AD  - School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 
      Guangzhou, 510006, PR China.
FAU - Xie, Xi
AU  - Xie X
AD  - Key Laboratory of Tropical Biological Resources of Ministry of Education, School 
      of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
FAU - Zhu, Jiaqi
AU  - Zhu J
AD  - School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 
      Guangzhou, 510006, PR China.
FAU - Yuan, Yijun
AU  - Yuan Y
AD  - Key Laboratory of Tropical Biological Resources of Ministry of Education, School 
      of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Song Li' 
      Academician Workstation of Hainan University (School of Pharmaceutical Sciences), 
      Yazhou Bay, Sanya, 572000, China.
FAU - He, Yue-Ming
AU  - He YM
AD  - School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 
      Guangzhou, 510006, PR China.
FAU - Huang, Yi-You
AU  - Huang YY
AD  - School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, PR 
      China; Key Laboratory of Tropical Biological Resources of Ministry of Education, 
      School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Song 
      Li' Academician Workstation of Hainan University (School of Pharmaceutical 
      Sciences), Yazhou Bay, Sanya, 572000, China. Electronic address: 
      hyyou@hainanu.edu.cn.
FAU - Luo, Hai-Bin
AU  - Luo HB
AD  - School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, PR 
      China; Key Laboratory of Tropical Biological Resources of Ministry of Education, 
      School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Song 
      Li' Academician Workstation of Hainan University (School of Pharmaceutical 
      Sciences), Yazhou Bay, Sanya, 572000, China. Electronic address: 
      luohb77@mail.sysu.edu.cn.
FAU - He, Xixin
AU  - He X
AD  - School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 
      Guangzhou, 510006, PR China. Electronic address: mark07@gzucm.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20220809
PL  - France
TA  - Eur J Med Chem
JT  - European journal of medicinal chemistry
JID - 0420510
RN  - 0 (Aminopyridines)
RN  - 0 (Benzamides)
RN  - 0 (Cyclopropanes)
RN  - 0 (Phosphodiesterase 4 Inhibitors)
RN  - 0P6C6ZOP5U (Roflumilast)
RN  - 64ALC7F90C (Dipyridamole)
RN  - 9042-14-2 (Dextran Sulfate)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
SB  - IM
MH  - Aminopyridines
MH  - Animals
MH  - Benzamides
MH  - Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry
MH  - Cyclopropanes
MH  - Dextran Sulfate
MH  - Dipyridamole/therapeutic use
MH  - Dogs
MH  - *Inflammatory Bowel Diseases/chemically induced/drug therapy
MH  - Mice
MH  - *Phosphodiesterase 4 Inhibitors/pharmacology/therapeutic use
OTO - NOTNLM
OT  - Inflammatory Bowel Diseases
OT  - Mangostanin
OT  - PDE4 inhibitor
OT  - Safety
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2022/08/20 06:00
MHDA- 2022/09/21 06:00
CRDT- 2022/08/19 18:28
PHST- 2022/05/15 00:00 [received]
PHST- 2022/07/19 00:00 [revised]
PHST- 2022/07/24 00:00 [accepted]
PHST- 2022/08/20 06:00 [pubmed]
PHST- 2022/09/21 06:00 [medline]
PHST- 2022/08/19 18:28 [entrez]
AID - S0223-5234(22)00533-5 [pii]
AID - 10.1016/j.ejmech.2022.114631 [doi]
PST - ppublish
SO  - Eur J Med Chem. 2022 Nov 15;242:114631. doi: 10.1016/j.ejmech.2022.114631. Epub 
      2022 Aug 9.