The design and synthesis of novel SGLT2 inhibitors: C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties.
The sodium glucose co-transporter 2 (SGLT2) has received considerable attention in recent years as a target for the treatment of type 2 diabetes mellitus. This report describes the design, synthesis and structure-activity relationship (SAR) of C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties as novel SGLT2 inhibitors. Compounds 5p and 33b demonstrated high potency in inhibiting SGLT2 and high selectivity against SGLT1. The in vitro ADMET properties of these compounds will also be discussed.
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Cheng
C
Guo
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Min
M
Hu
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Russell J
RJ
DeOrazio
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Alexander
A
Usyatinsky
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Kevin
K
Fitzpatrick
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Zhenjun
Z
Zhang
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Jun-Ho
JH
Maeng
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Douglas B
DB
Kitchen
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Susan
S
Tom
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Michele
M
Luche
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Yuri
Y
Khmelnitsky
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Andrew J
AJ
Mhyre
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
Peter R
PR
Guzzo
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA. Electronic address: shuang.Liu@amriglobal.com.
Shuang
S
Liu
D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D006027:Glycosides; D011728:Pyridones; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014230:Triazoles; C001419:hydroxyphenytoin; D010672:Phenytoin
Canagliflozin; Dapagliflozin; Glucoside; Hydantoin; SGLT2; Triazolopyridinone