Bioorganic & Medicinal Chemistry Letters
Modification on the O-glucoside of Sergliflozin-A: A new strategy for
SGLT2 inhibitor design
a,
Xuefeng Cao a,y, Wenpeng Zhang b,y, Xu Yan a, Zhi Huang a, Zhenqing Zhang b, Peng Wang a, , Jie Shen
⇑
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a State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China
b State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Poor pharmacokinetic stability is one of the issues of O-glucoside SGLT2 inhibitors in clinical trials, hence
C-glucoside inhibitors have been developed and extensively applied. Herein, we provided an alternative
approach to improve the pharmacokinetic stability of such inhibitors. Nine derivatives of Sergliflozin-A
with modifications on the O-glucoside fragment were prepared, among which the 4-O-methyl derivative
exhibited similar pharmacodynamics potency in excreted glucose urine test. Most attractively, signifi-
cantly increased pharmacokinetic stability was observed for 4-O-methyl derivative of O-glucosides.
This work proved that modification on the O-glucoside fragment could be a promising approach to the
future SGLT2 inhibitor design.
Received 18 February 2016
Revised 14 March 2016
Accepted 16 March 2016
Available online xxxx
Keywords:
SGLT2 inhibitor
Sergliflozin-A
Ó 2016 Elsevier Ltd. All rights reserved.
O-Glucoside
Pharmacokinetic stability
During the past few years, great efforts have been devoted to
develop sodium glucose co-transporter 2 (SGLT2) inhibitors as a
new class of drugs for the treatment of diabetes.1–8 These com-
pounds (Fig. 1) could effectively relieve diabetic hyperglycemia
via lowering the renal glucose reabsorption.9–11 Phlorizin, isolated
from the bark of apple roots, was the first O-glucoside compound
which can inhibit both SGLT1 and SGLT2.12,13 Other O-glucoside
inhibitors with high selectivity towards SGLT2 were also devel-
oped. However, most of O-glucoside inhibitors, for example, T-
109514 and Sergliflozin,15,16 were suspended. Currently, majority
of the launched SGLT2 inhibitors, e.g., Dapagliflozin,4
Empagliflozin6,17 and Canagliflozin,7,18 are C-glucosides. This could
at least partially be attributed to the poor metabolic stability of O-
glucosides, arising from the glucosidase mediated hydrolysis.
Alternatively, it is understandable that modification on the O-
glucoside fragment may affect the substrate-glucosidase binding,
thus could also help to improve in vivo stability. In this work, tak-
ing Sergliflozin-A (active form of Sergliflozin) as a parent structure,
a series of derivatives with modification on hydroxyl groups (e.g.,
methylated, fluorine-substituted, deoxidized) of its O-glycoside
were synthesized (Fig. 2) and evaluated.
mide donor A0 was coupled with the aglycon acceptor S219 to
afford the intermediate A1 which was deacetylated to give the
compound A, Sergliflozin-A. Promoted by boron trifluoride ether-
ate, the glycosyl donor B019 was coupled with S2 to provide the
intermediate B1, which was sequentially deacetylated and methy-
lated at its O2 position to afford the 2-O-methyl 3,4,6-tri-O-benzyl
derivative B3. Pd-catalyzed debenzylation of B3 gave the com-
pound B. The 2-fluorinated glucosyl Schimidt donor C019 was cou-
pled with S2 to provide the intermediate C1 as an unseparable a/b
mixture.19 After the sequential debenzylation, acetylation and flash
chromatography separation, C1 was converted to the intermediate
C3 as a pure b isomer, which was converted to the compound C by
the global deacetylation. The compounds D, E, I were prepared
from the 1-acetylated donors D0,19 E019 and I019 respectively via
a similar two-step procedure, including a glycosylation reaction
followed by a global deacetylation. The compound F was prepared
from compound A in 5 steps. Specifically, after the 4,6-benzylide-
nation and 2,3-benzylation reactions, A was converted to the inter-
mediate F2. Regioselective and reductive ring opening of the 4,6-
benzylidene of F2 gave the intermediate F3 whose 4-hydroxyl
group was then methylated with MeI. Then the obtained interme-
diate was converted to the product F via global debenzylation.
Regioselective benzoylation of the thioglycoside G019 gave the
intermediate G1 whose 4-hydroxyl group was thiocarbonylated
to give the intermediate G2. Barton–McCombie radical reduction
was then performed to convert G2 to the 4-deoxy intermediate,
which was converted to 1-acetylated donor compound G3. Then
G3 was coupled with S2 to afford the glycosylation product G4,
The synthesis of Sergliflozin-A and its nine derivatives were
illustrated in Scheme 1. Briefly, the peracetylated
a-glucosyl bro-
⇑
Corresponding authors.
Shen).
y
Authors contributed equally to this work.
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.