PMID- 35381556
OWN - NLM
STAT- MEDLINE
DCOM- 20220502
LR  - 20220531
IS  - 1090-2120 (Electronic)
IS  - 0045-2068 (Linking)
VI  - 123
DP  - 2022 Jun
TI  - Design, synthesis and evaluation of a series of novel long-acting dipeptidyl 
      peptidase-4 inhibitors for the treatment of type 2 diabetes.
PG  - 105767
LID - S0045-2068(22)00172-9 [pii]
LID - 10.1016/j.bioorg.2022.105767 [doi]
AB  - Type 2 diabetes mellitus (T2DM) is one of the most popular chronic diseases 
      around the whole world. To improve the compliance of patients, long-acting 
      antidiabetic drugs needed to be developed. Dipeptidyl peptidase-4 (DPP-4) 
      inhibitors are becoming increasingly important in the T2DM treatment due to the 
      favorable properties. In the present study, a series of new substituted 
      dihydropyrido [4',3':3,4] pyrazolo [1,5-a] 
      pyrimidin-9(10H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine were 
      designed and synthesized as potent DPP-4 inhibitors. All compounds were 
      characterized by (1)H NMR, (13)C NMR and HRMS and were evaluated in vitro. The 
      inhibitory activity ranged from 0.43 to 12.70 muM while the inhibitory activity of 
      positive control (omarigliptin) was 3.63 muM on DPP-4 in Caco-2 cells. Then 
      pharmacokinetic studies were carried out in rats and compound 6c was finally 
      selected for the further study because of its better pharmacokinetic profile. 
      Additionally, preclinical pharmacological study of compound 6c exhibited 
      extraordinary efficacy in vivo and good safety profile. In conclusion, compound 
      6c was considered as a promising DPP-4 inhibitor, which could be taken once a 
      week or once every two weeks for the treatment of T2DM. More comprehensive 
      researches will be carried out in the future for the further development of 
      compound 6c.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Lin, Chao
AU  - Lin C
AD  - Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute 
      of Materia Medica, Yantai 264000, China.
FAU - Kong, Ying
AU  - Kong Y
AD  - Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute 
      of Materia Medica, Yantai 264000, China.
FAU - Wang, Furong
AU  - Wang F
AD  - School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation 
      (Yantai University), Ministry of Education, Collaborative Innovation Center of 
      Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, 
      Yantai University, Yantai 264005, China.
FAU - Rong, Rong
AU  - Rong R
AD  - Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute 
      of Materia Medica, Yantai 264000, China.
FAU - Li, Xiangping
AU  - Li X
AD  - Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute 
      of Materia Medica, Yantai 264000, China.
FAU - Xiao, Rensong
AU  - Xiao R
AD  - School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation 
      (Yantai University), Ministry of Education, Collaborative Innovation Center of 
      Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, 
      Yantai University, Yantai 264005, China.
FAU - Wu, Ziqi
AU  - Wu Z
AD  - School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation 
      (Yantai University), Ministry of Education, Collaborative Innovation Center of 
      Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, 
      Yantai University, Yantai 264005, China.
FAU - Zhang, Qiuyan
AU  - Zhang Q
AD  - School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation 
      (Yantai University), Ministry of Education, Collaborative Innovation Center of 
      Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, 
      Yantai University, Yantai 264005, China; Yantai Key Laboratory of Nanomedicine & 
      Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China. 
      Electronic address: qyzhang@yimm.ac.cn.
FAU - Wang, Lin
AU  - Wang L
AD  - School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation 
      (Yantai University), Ministry of Education, Collaborative Innovation Center of 
      Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, 
      Yantai University, Yantai 264005, China. Electronic address: 
      rushanwanglin@126.com.
LA  - eng
PT  - Journal Article
DEP - 20220326
PL  - United States
TA  - Bioorg Chem
JT  - Bioorganic chemistry
JID - 1303703
RN  - 0 (Dipeptidyl-Peptidase IV Inhibitors)
RN  - 0 (Hypoglycemic Agents)
RN  - EC 3.4.14.5 (DPP4 protein, human)
RN  - EC 3.4.14.5 (Dipeptidyl Peptidase 4)
SB  - IM
MH  - Animals
MH  - Caco-2 Cells
MH  - *Diabetes Mellitus, Type 2/drug therapy
MH  - Dipeptidyl Peptidase 4
MH  - *Dipeptidyl-Peptidase IV Inhibitors/chemistry/pharmacology/therapeutic use
MH  - Humans
MH  - Hypoglycemic Agents/pharmacokinetics/therapeutic use
MH  - Rats
OTO - NOTNLM
OT  - Dipeptidyl peptidase-4
OT  - Long-acting DPP-4 inhibitors
OT  - Omarigliptin
OT  - Type 2 diabetes mellitus
EDAT- 2022/04/06 06:00
MHDA- 2022/05/03 06:00
CRDT- 2022/04/05 20:14
PHST- 2021/08/15 00:00 [received]
PHST- 2022/01/25 00:00 [revised]
PHST- 2022/03/24 00:00 [accepted]
PHST- 2022/04/06 06:00 [pubmed]
PHST- 2022/05/03 06:00 [medline]
PHST- 2022/04/05 20:14 [entrez]
AID - S0045-2068(22)00172-9 [pii]
AID - 10.1016/j.bioorg.2022.105767 [doi]
PST - ppublish
SO  - Bioorg Chem. 2022 Jun;123:105767. doi: 10.1016/j.bioorg.2022.105767. Epub 2022 
      Mar 26.