Synthesis and biological evaluation of novel benzyl-substituted (S)-phenylalanine derivatives as potent dipeptidyl peptidase 4 inhibitors.
A series of novel benzyl-substituted (S)-phenylalanine derivatives were synthesized and evaluated for their dipeptidyl peptidase 4 (DPP-4) inhibitory activity and selectivity. It was found that most synthesized target compounds were potent DPP-4 inhibitors with IC50 values in 3.79-25.52 nM, which were significantly superior to that of the marketed drug sitagliptin. Furthermore, the 4-fluorobenzyl substituted phenylalanine derivative 6g not only displayed the potent DPP-4 inhibition with an IC50 value of 3.79 nM, but also showed better selectivity against DPP-4 over other related enzymes including DPP-7, DPP-8, and DPP-9. In an oral glucose tolerance test (OGTT) in normal Sprague Dawley rats, compound 6g reduced blood glucose excursion in a dose-dependent manner.
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Yang
Y
Liu
Meimei
M
Si
Li
L
Tang
Shihao
S
Shangguan
Haoshu
H
Wu
Jia
J
Li
Peng
P
Wu
Xiaodong
X
Ma
Tao
T
Liu
Yongzhou
Y
Hu
D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D005951:Glucose Tolerance Test; D062105:Molecular Docking Simulation; D010649:Phenylalanine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011719:Pyrazines / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068900:Sitagliptin Phosphate; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D010649:Phenylalanine; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate
(S)-Phenylalanine derivatives; 1,2,3-Triazole; Dipeptidyl peptidase 4 inhibitors; Selectivity; Type 2 diabetes