Bexagliflozin [(2S,3R,4R,5S,6R)-2-[4-chloro-3-({4-[2-(cyclopropyloxy)
ethoxy] phenyl} methyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol] is
an orally administered drug for the treatment of Type 2 Diabetes Mellitus
(T2DM) and is classified as a Sodium Glucose co-Transporter 2 (SGLT2)
Inhibitor. Bexagliflozin exhibited an IC50 of 2
nM with a 2435-fold selectivity ratio against SGLT2 compared to SGLT1.
Chemically, Bexagliflozin falls in the C-aryl glucoside class and synthesized via EGT1474 [1, 2]. EGT1474 is the
co-crystalline form of Bexagliflozin with L-proline in 1:2
stoichiometry. The mass ratio of EGT1474 to Bexagliflozin is
1.5:1 [1, 2]. Bexagliflozin is in Phase 2b study to evaluate the
effect of bexagliflozin tablets in subjects with type 2 diabetes mellitus.
The inhibitory effects of Bexagliflozin for human SGLT1 and SGLT2
were evaluated in an AMG uptake assay and the in vivo efficacy of
treatment with Bexagliflozin was investigated in rats and dogs
after a single dose and in db/db mice after chronic administration. The IC50 values
for Bexagliflozin against human SGLT1 and SGLT2 are 5.6 uM and 2 nM,
respectively. In normal rats and dogs a saturable urinary glucose
excretion was produced with an ED50 of 0.38 and 0.09
mg/kg, respectively. Following chronic administration to db/db mice, Bexagliflozin dose-dependently
reduced HbA1c and blood glucose concentration without affecting body mass or
insulin level. Additionally, Bexagliflozin significantly prolonged
the median survival of SHRSP rats [1].
The activity of Bexagliflozin is
as follows:
IC50 (Human
SGLT1 Activity, AMG Uptake Assay) = 5.6 ± 0.59 uM
IC50 (Human SGLT2 Activity, AMG Uptake Assay) = 0.002 ± 0.001 uM
IC50 (Human SGLT2 Activity, AMG Uptake Assay) = 0.002 ± 0.001 uM
The activity of EGT1474 is
as follows:
IC50 (Human
SGLT1 Activity, AMG Uptake Assay) = 6.8 ± 0.47 uM
IC50 (Human SGLT2 Activity, AMG Uptake Assay) = 0.003 ± 0.001 uM
IC50 (Human SGLT2 Activity, AMG Uptake Assay) = 0.003 ± 0.001 uM
Common Name: Bexagliflozin
Synonym: THR1442; THR-1442, EGT0001442; EGT1442
CAS Number: 1118567-05-7
Mechanism of Action: SGLT2 Inhibitor; Sodium Glucose co-Transporter 2 Inhibitor
Indication: Treatment of Type 2 Diabetes; Treatment of T2DM
Development Stage: Phase II
Originator: Egret Pharma (Shanghai)\Theracos Inc.
Synonym: THR1442; THR-1442, EGT0001442; EGT1442
CAS Number: 1118567-05-7
IUPAC Name: (2S,3R,4R,5S,6R)-2-[4-chloro-3-({4-[2-(cyclopropyloxy)ethoxy]phenyl}
methyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol
SMILES:c1cc(ccc1Cc2cc(ccc2Cl)[C@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO)O)O)O)
OCCOC4CC4Mechanism of Action: SGLT2 Inhibitor; Sodium Glucose co-Transporter 2 Inhibitor
Indication: Treatment of Type 2 Diabetes; Treatment of T2DM
Development Stage: Phase II
Originator: Egret Pharma (Shanghai)\Theracos Inc.
The sodium-dependent (“active”)
glucose cotransporters (SGLTs), including SGLT1 (found predominantly in the
intestinal brush border) and SGLT2 (localized in the renal proximal tubule),
are being considered as therpeutic targets. In particular, SGLT2 has been found
to be responsible for the majority of glucose reuptake by the kidneys
Inhibition of renal SGLT is now considered a useful approach to treating
hyperglycemia by increasing the amount of glucose excreted in the urine. The
potential of this therapeutic approach is further supported by recent findings
that mutations in the SGLT2 gene occur in cases of familial renal glucosuria,
an apparently benign syndrome characterized by urinary glucose excretion in the
presence of normal serum glucose levels and the absence of general renal
dysfunction or other disease.
Therefore, compounds which inhibit SGLT, particularly SGLT2, are promising
candidates for use as antidiabetic drugs. In addition, since cancer cells show
increased glucose uptake in comparison to their normal counterparts, SGLT
inhibition has been proposed as a method for treating cancer by starving cancer
cells. For example, studies suggest that SGLT2 plays a role in glucose uptake
in metastatic lesions of lung cancer. Thus, SGLT2 inhibitors may also be useful
as anticancer agents [2].
Plasma insulin levels were not affected by the administration
of Bexagliflozin to diabetic animals, which indicates that the
blood glucose lowering effect of Bexagliflozin does not rely on
insulin secretion or insulin action. Thus, agents of this class could be
effective in a wide variety of patients.
Bexagliflozin increases urinary glucose excretion in healthy rats and dogs. A
sustained effect in reducing blood glucose concentration and HbA1c level was
demonstrated in diabetic mice. No body weight gain, stimulation of insulin
secretion or GI effects were observed during the study in diabetic mice,
suggesting that Bexagliflozin has low risk for provoking
the weight gain, hypoglycemia or diarrhea often elicited by current
anti-diabetic medications. Further, treatment with Bexagliflozin significantly
prolonged the survival of SHRSP rats on a stroke-promoting diet.
Therefore, Bexagliflozin may provide an efficacious
treatment strategy for patients with the comorbidities of diabetes and
hypertension [1].
References:
1. Wang, Y.-X.; et. al. EGT1442, a potent and selective SGLT2
inhibitor, attenuates blood glucose and HbA1c levels in db/db mice and prolongs
the survival of stroke-prone rats. Pharmacol Res 2011, 63(4), 284-293.
2. Xu, B.; et. al. Process for the preparation of
benzylbenzene sglt2 inhibitors. US20130267694A1
3. ClinicalTrials.gov A Dose
Range Finding Study to Evaluate the Effect of Bexagliflozin Tablets in Subjects
With Type 2 Diabetes Mellitus. NCT02390050 (retrieved on 26-03-2015).
4. ClinicalTrials.gov Safety and Efficacy Study of
EGT0001442 in Subjects With Type 2 Diabetes Mellitus. NCT01029704 (retrieved on 26-03-2015).
5. ClinicalTrials.gov
Efficacy and Safety of EGT0001442 in Patients With Type 2 Diabetes Mellitus. NCT01377844 (retrieved on
26-03-2015).