Bexagliflozin

Identification

Summary

Bexagliflozin is a sodium-glucose co-transporter 2 inhibitor used to improve glycemic control in patients with type 2 diabetes mellitus.

Brand Names

Brenzavvy

Generic Name

Bexagliflozin

DrugBank Accession Number

DB12236

Background

Bexagliflozin is a highly specific and potent sodium-glucose co-transporter 2 (SGLT2) inhibitor.^1,2,6 Similar to other SGLT2 inhibitors, bexagliflozin contains three basic moieties: glucose, two benzene rings and a methylene bridge.² SGLT2 is responsible for 60% to 90% of renal glucose re-uptake, and unlike other isoforms such as SGLT1, SGLT2 is mainly expressed in the kidney.¹ By inhibiting SGLT2, bexagliflozin reduces renal reabsorption of filtered glucose and increases urinary glucose excretion, which reduces blood glucose levels independently of insulin sensitivity.^4,6 In January 2023, bexagliflozin was approved by the FDA for the treatment of adults with type 2 diabetes. Its use is not recommended in patients with type 1 diabetes since it may increase their risk of diabetic ketoacidosis.⁶

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Bexagliflozin (DB12236)

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Weight

Average: 464.94
Monoisotopic: 464.160181

Chemical Formula

C₂₄H₂₉ClO₇

Synonyms

• (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
• Bexagliflozin
• D-glucitol, 1,5-anhydro-1-C-(4-chloro-3-((4-(2-(cyclopropyloxy)ethoxy)phenyl)methyl)phenyl)-, (1s)-

External IDs

• EGT-1442
• EGT0001442
• EGT1442
• THR-1442
• THR1442

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Pharmacology

Indication

Bexagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.⁶

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Adjunct therapy in management of	Type 2 diabetes mellitus		••••••••••••	•••••		••••••

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Contraindications & Blackbox Warnings

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Pharmacodynamics

Healthy subjects and adults with type 2 diabetes mellitus given single or multiple doses of bexagliflozin had dose-dependent increases in urinary glucose excretion (UGE) accompanied by increases in urine volume. A 20 mg bexagliflozin dose can provide near-maximal UGE, and elevated UGE values are maintained with multiple-dose administration. Bexagliflozin does not cause clinically significant QTc interval prolongation at 5 times the recommended dose.⁶

The use of bexagliflozin may cause ketoacidosis, volume depletion, urosepsis, pyelonephritis, necrotizing fasciitis of the perineum and genital mycotic infections. There is also an increased incidence of lower limb amputation in patients treated with bexagliflozin compared to those receiving a placebo. In addition, the use of bexagliflozin in patients treated with insulin and insulin secretagogues may increase the risk of hypoglycemia.⁶

Mechanism of action

Bexagliflozin is a highly selective sodium–glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 is located in the proximal renal tubule, a part of the kidney where most reabsorption takes place, and they transport glucose and sodium from the tubular lumen to the epithelium. By inhibiting SGLT2, bexagliflozin reduces glucose reabsorption in the kidney and promotes its excretion in urine. Therefore, in patients with type 2 diabetes mellitus (T2DM), bexagliflozin reduces blood glucose levels independently of insulin sensitivity.^4,6

Aside from improving glycemic control, bexagliflozin may also reduce body weight, systolic blood pressure, and albuminuria.⁵ The mechanism of action for these other effects have not been fully elucidated, but it is possible that they depend on the initial natriuresis caused by bexagliflozin, followed by a change in tissue sodium handling.⁴

Target	Actions	Organism
ASodium/glucose cotransporter 2	inhibitor	Humans

Absorption

Healthy subjects and adult patients with type 2 diabetes mellitus given bexagliflozin have similar pharmacokinetic profiles. In a fasted state, the mean C_max and AUC_0-∞ of bexagliflozin were 134 ng/mL and 1,162 ng·h/mL, respectively. Bexagliflozin does not follow a time-dependent pharmacokinetic profile, and after multiple doses, approximately up to 20% is accumulated in plasma. The peak plasma concentration of bexagliflozin is reached between 2 and 4 hours after oral administration. This timing can be delayed if bexagliflozin is taken after a meal or with medications that slow gastric emptying. Between single doses of 3 mg and 90 mg (0.15 to 4.5 times the recommended dose), the plasma C_max and AUC of bexagliflozin increase in a dose-proportional manner.⁶

Compared to dosing in the fasted state, consuming a standard high-fat, high-caloric meal leads to a 31% and 10% higher C_max and AUC, respectively. Under these conditions, the median T_max was increased to 5 hours. The effects of food on bexagliflozin pharmacokinetics are not considered clinically relevant.⁶

Volume of distribution

Bexagliflozin has an apparent volume of distribution of 262 L.⁶

Protein binding

Approximately 93% of bexagliflozin is bound to plasma protein.⁶

Metabolism

Bexagliflozin is metabolized in the liver mainly by UGT1A9 and, to a lesser extent, CYP3A. In healthy volunteers given an oral [14C]-bexagliflozin solution, the 3'-O-glucuronide, a pharmacologically inactive metabolite, constituted 32.2% of the parent compound AUC. The rest of the bexagliflozin metabolites contributed less than 10% of the parent AUC. None of the metabolites are expected to have clinically relevant pharmacological effects.^3,6

Hover over products below to view reaction partners

• Bexagliflozin
  • EGT0002149
  • EGT0001494
  • EGT0001301
  • EGT0001663

Route of elimination

Bexagliflozin is mainly eliminated through feces and urine. In healthy subjects given an oral [14C]-bexagliflozin solution, 91.6% of input radioactivity was recovered. Of this amount, 51.1% was recovered in feces, mainly as the parent compound, while 40.5% was recovered in urine, mostly as the 3'-O-glucuronide. The proportions of input radioactivity recovered as bexagliflozin in urine and feces were 1.5% and 28.7%, respectively.⁶

Half-life

Bexagliflozin has an apparent terminal elimination half-life of approximately 12 hours.⁶

Clearance

Population pharmacokinetic modeling has shown that the apparent oral clearance of bexagliflozin is 19.1 L/h.⁶

Adverse Effects

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Toxicity

In case of a bexagliflozin overdose, the FDA product label recommends contacting the Poison Help line or a medical toxicologist for additional overdosage management recommendations. Usual supportive measures based on the patient’s clinical status should be employed. The removal of bexagliflozin by hemodialysis has not been evaluated.⁶ Carcinogenicity was evaluated in mice and rats, and no drug-related neoplastic findings were reported at up to the highest doses, which corresponded to 156 times (mice) and 68 times (rats) the clinical dose of bexagliflozin (20 mg) based on AUC. In vitro and in vivo studies found that bexagliflozin was not mutagenic or clastogenic. Fertility studies done in male and female rats showed that bexagliflozin had no effects on mating, fertility or early embryonic development at up to 200 mg/kg/day, which corresponded to 280 and 439 times the clinical dose of bexagliflozin in males and females, respectively.⁶

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Acarbose	Bexagliflozin may increase the hypoglycemic activities of Acarbose.
Acebutolol	The therapeutic efficacy of Bexagliflozin can be increased when used in combination with Acebutolol.
Acetazolamide	The therapeutic efficacy of Bexagliflozin can be increased when used in combination with Acetazolamide.
Acetohexamide	Bexagliflozin may increase the hypoglycemic activities of Acetohexamide.
Acetyl sulfisoxazole	The therapeutic efficacy of Bexagliflozin can be increased when used in combination with Acetyl sulfisoxazole.

Food Interactions

• Take with or without food. Peak plasma concentrations of bexagliflozin can be delayed if taken after a meal; however, the effects of food on bexagliflozin pharmacokinetics are not considered clinically relevant.

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International/Other Brands

Brenzavvy (TheracosBio)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Brenzavvy	Tablet	20 mg/1	Oral	Golden State Medical Supply, Inc.	2023-01-20	Not applicable
Brenzavvy	Tablet	20 mg/1	Oral	TheracosBio, LLC	2023-07-13	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Bexagliflozin	Tablet	20 mg/1	Oral	TheracosBio, LLC	2024-03-19	Not applicable

Categories

Drug Categories

• Benzene Derivatives
• Blood Glucose Lowering Agents
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Diabetes Mellitus, Type 2, drug therapy
• Diuretics
• Drugs Used in Diabetes
• Glycosides
• Oral Hypoglycemics
• P-glycoprotein substrates
• Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors
• Sodium-Glucose Transport Proteins, antagonists & inhibitors
• Sodium-Glucose Transporter 2 Inhibitors
• UGT1A1 Substrates
• UGT1A9 Substrates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as phenolic glycosides. These are organic compounds containing a phenolic structure attached to a glycosyl moiety. Some examples of phenolic structures include lignans, and flavonoids. Among the sugar units found in natural glycosides are D-glucose, L-Fructose, and L rhamnose.

Kingdom

Organic compounds

Super Class

Organic oxygen compounds

Class

Organooxygen compounds

Sub Class

Carbohydrates and carbohydrate conjugates

Direct Parent

Phenolic glycosides

Alternative Parents

Diphenylmethanes / Hexoses / C-glycosyl compounds / Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Chlorobenzenes / Oxanes / Aryl chlorides / 1,2-diols / Secondary alcohols / Dialkyl ethers / Oxacyclic compounds / Hydrocarbon derivatives / Primary alcohols / Organochlorides

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Substituents

1,2-diol / Alcohol / Alkyl aryl ether / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Benzenoid / C-glycosyl compound / Chlorobenzene / Dialkyl ether / Diphenylmethane / Ether / Halobenzene / Hexose monosaccharide / Hydrocarbon derivative / Monocyclic benzene moiety / Monosaccharide / Organochloride / Organohalogen compound / Organoheterocyclic compound / Oxacycle / Oxane / Phenol ether / Phenolic glycoside / Phenoxy compound / Polyol / Primary alcohol / Secondary alcohol

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Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

EY00JF42FV

CAS number

1118567-05-7

InChI Key

BTCRKOKVYTVOLU-SJSRKZJXSA-N

InChI

InChI=1S/C24H29ClO7/c25-19-8-3-15(24-23(29)22(28)21(27)20(13-26)32-24)12-16(19)11-14-1-4-17(5-2-14)30-9-10-31-18-6-7-18/h1-5,8,12,18,20-24,26-29H,6-7,9-11,13H2/t20-,21-,22+,23-,24+/m1/s1

IUPAC Name

(2S,3R,4R,5S,6R)-2-(4-chloro-3-{[4-(2-cyclopropoxyethoxy)phenyl]methyl}phenyl)-6-(hydroxymethyl)oxane-3,4,5-triol

SMILES

OC[C@H]1O[C@H]([C@H](O)[C@@H](O)[C@@H]1O)C1=CC=C(Cl)C(CC2=CC=C(OCCOC3CC3)C=C2)=C1

References

Synthesis Reference

Gharpure, M., et al. (2018). A process for the preparation of SGLT2 inhibitor and intermediates thereof (WO 2018/207113 A1). World Intellectual Property Organization. https://patentimages.storage.googleapis.com/8a/8f/d2/343c7232594398/WO2018207113A1.pdf

General References

1. Zhang W, Welihinda A, Mechanic J, Ding H, Zhu L, Lu Y, Deng Z, Sheng Z, Lv B, Chen Y, Roberge JY, Seed B, Wang YX: EGT1442, a potent and selective SGLT2 inhibitor, attenuates blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone rats. Pharmacol Res. 2011 Apr;63(4):284-93. doi: 10.1016/j.phrs.2011.01.001. Epub 2011 Jan 5. [Article]
2. Azzam O, Carnagarin R, Lugo-Gavidia LM, Nolde J, Matthews VB, Schlaich MP: Bexagliflozin for type 2 diabetes: an overview of the data. Expert Opin Pharmacother. 2021 Nov;22(16):2095-2103. doi: 10.1080/14656566.2021.1959915. Epub 2021 Jul 29. [Article]
3. Zhang W, Li X, Ding H, Lu Y, Stilwell GE, Halvorsen YD, Welihinda A: Metabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans. Xenobiotica. 2020 May;50(5):559-569. doi: 10.1080/00498254.2019.1654634. Epub 2019 Aug 27. [Article]
4. Cowie MR, Fisher M: SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020 Dec;17(12):761-772. doi: 10.1038/s41569-020-0406-8. Epub 2020 Jul 14. [Article]
5. Allegretti AS, Zhang W, Zhou W, Thurber TK, Rigby SP, Bowman-Stroud C, Trescoli C, Serusclat P, Freeman MW, Halvorsen YC: Safety and Effectiveness of Bexagliflozin in Patients With Type 2 Diabetes Mellitus and Stage 3a/3b CKD. Am J Kidney Dis. 2019 Sep;74(3):328-337. doi: 10.1053/j.ajkd.2019.03.417. Epub 2019 May 14. [Article]
6. FDA Approved Drug Products: BRENZAVVY (bexagliflozin) tablets for oral use [Link]

External Links

PubChem Compound

25195624

PubChem Substance

347828515

ChemSpider

26609013

BindingDB

50349249

RxNav

2627044

ChEMBL

CHEMBL1808388

ZINC

ZINC000059047505

Wikipedia

Bexagliflozin

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Recruiting	Treatment	Sleep Apnea	1
3	Completed	Treatment	Type 2 Diabetes Mellitus	6
3	Recruiting	Treatment	Type 2 Diabetes Mellitus	1
2	Completed	Treatment	Diabetes Mellitus	1
2	Completed	Treatment	Type 2 Diabetes Mellitus	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	20 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US10533032	No	2020-01-14	2031-07-03
US8802637	No	2014-08-12	2028-08-22
US8106021	No	2012-01-31	2028-08-22
US7838499	No	2010-11-23	2029-01-30
US8987323	No	2015-03-24	2032-05-14
US10981942	No	2021-04-20	2031-06-13

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Slightly soluble	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.0565 mg/mL	ALOGPS
logP	2.33	ALOGPS
logP	2.17	Chemaxon
logS	-3.9	ALOGPS
pKa (Strongest Acidic)	12.57	Chemaxon
pKa (Strongest Basic)	-3	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	7	Chemaxon
Hydrogen Donor Count	4	Chemaxon
Polar Surface Area	108.61 Å2	Chemaxon
Rotatable Bond Count	9	Chemaxon
Refractivity	118.44 m3·mol-1	Chemaxon
Polarizability	49.38 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-014j-4004900000-06fbcebcf1cd445cfbaa
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0bti-5009500000-b024a6d4339c7f287446
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a6r-1014900000-260def8cddf68decee41
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-01q9-9007200000-d822f4e164e6c7bd83d4
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-052b-6396500000-20b44dbbab012b04bae0
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-057i-9054100000-4394c494593ef6a411be
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	204.12209	predicted	DeepCCS 1.0 (2019)
[M+H]+	206.4066	predicted	DeepCCS 1.0 (2019)
[M+Na]+	212.31992	predicted	DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.

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Details1. Sodium/glucose cotransporter 2

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Low-affinity glucose:sodium symporter activity

Specific Function

Sodium-dependent glucose transporter. Has a Na(+) to glucose coupling ratio of 1:1.Efficient substrate transport in mammalian kidney is provided by the concerted action of a low affinity high capac...

Gene Name

SLC5A2

Uniprot ID

P31639

Uniprot Name

Sodium/glucose cotransporter 2

Molecular Weight

72895.995 Da

References

1. Zhang W, Welihinda A, Mechanic J, Ding H, Zhu L, Lu Y, Deng Z, Sheng Z, Lv B, Chen Y, Roberge JY, Seed B, Wang YX: EGT1442, a potent and selective SGLT2 inhibitor, attenuates blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone rats. Pharmacol Res. 2011 Apr;63(4):284-93. doi: 10.1016/j.phrs.2011.01.001. Epub 2011 Jan 5. [Article]
2. Azzam O, Carnagarin R, Lugo-Gavidia LM, Nolde J, Matthews VB, Schlaich MP: Bexagliflozin for type 2 diabetes: an overview of the data. Expert Opin Pharmacother. 2021 Nov;22(16):2095-2103. doi: 10.1080/14656566.2021.1959915. Epub 2021 Jul 29. [Article]
3. FDA Approved Drug Products: BRENZAVVY (bexagliflozin) tablets for oral use [Link]

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Drug created at October 20, 2016 21:41 / Updated at June 06, 2023 12:13