Thursday, March 26, 2015

Drugs in Clinical Pipeline: Bexagliflozin

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
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
Common Name: Bexagliflozin
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) OCCOC4CC4
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.
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].
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. 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. Safety and Efficacy Study of EGT0001442 in Subjects With Type 2 Diabetes Mellitus. NCT01029704 (retrieved on 26-03-2015).
5. Efficacy and Safety of EGT0001442 in Patients With Type 2 Diabetes Mellitus. NCT01377844  (retrieved on 26-03-2015).