Sodium-glucose transporter (SGLT2) inhibition: A potential target for treatment of type-2 Diabetes Mellitus with Natural and Synthetic compounds

Figures & data

Figure 1. Describes the Glucose renal reabsorption process and the mechanism of SGLT2 inhibitors (The Figures has been created by the author).

Table 1. List of Synthetic drugs investigated for Antidiabetic action through SGLT2 inhibition.

Phlorizin-derived synthetic SGLT-2 inhibitor- O glucoside analogs
S.no	Chemical Name	Trade name/IUPAC	Patented by company/Manufacturer	Pharmacokinetics			Dose	IC50 for SGLT1(nm)	IC50 for SGLT2(nm)	Changes in Parameter	Additive /synergistic therapy	Adverse effects	Ref
				t1/2(hrs)	Metabolic pathways	Excretion
1.	Remagliflozin	GSK189075/ethyl [(2 R,3S,4S,5 R,6S)-3,4,5-trihydroxy-6-[5-methyl-1-propan-2-yl-4-[(4-propan-2-yloxyphenyl)methyl]pyrazol-3-yl]oxyoxan-2-yl]methyl carbonate	Kissei Pharmaceuticals	1.5–1.9	GSK333081,P450(CYP)	Urine	250 mg	–	–	↓ weight loss, ↑ UGE, ↓ volume depletion	Metformin, Diuretics (Frusemide),(ketoconazole)	UTI, Vulvovaginitis, balanitis	[15,44]
Phlorizin-derived synthetic SGLT-2 inhibitor- C glucoside analogs
2.	Dapagliflozin	Forxiga/(2S,3 R,4 R,5S,6 R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol	Bristol-Myers Squibb	8–12.4	UGT1A9	3-O-glucuronide (61%) in urine	5 mg	1400	1.2	↓ Hb1Ac level, ↓weight loss, ↓hyperglycemia	Metformin, simvastatin, valsartan, digoxin, warfarin, etc.	Urinary and genital tract infections	[45–47]
3.	Canagliflozin	Invokana or Sulisent/(2S,3 R,4 R,5S,6 R)-2-[3-[[5-(4-fluorophenyl)thiophen-2-yl]methyl]-4-methylphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol	Jansen Pharmaceuticals	10.6	UGT1A9,UGT2B4	As metabolite M5 in urine	100–300 mg	1550	6.8	↓ in Hb1Ac, ↓body weight	Antihyperglycemic agents such as Metformin etc.	Plasma glucose postprandial Glucose, body weight, and systolic blood pressure	[45,47–49]
4.	Empagliflozin	Jardiance /(2S,3 R,4 R,5S,6 R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol	Boehringer Ingelheim and Eli Lilly	12.4	UGT2B7, UGT1A3	Unchanged in urine and feces	10–25 mg	8300	3.1	Improvement in glycemic control, ↓ body weight and BP,	Pioglitazone with metformin, metformin and sulfonylurea, and metformin	Urinary Tract infections, volume depletions acute renal failure, hyperkalemia, Risk of CVD	[23,45,47,50]
5.	Ertugliflozin	Steglatro/(1S,2S,3S,4 R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol	Merck & Co.	16.6	UGT1A9,UGT2B7	Unchanged in urine	5–15 mg	1960	0.877	↓hypoglycemia, ↓UTI, ↓ body weight, and BP	Metformin, sitagliptin, and sulfonylureas, in addition to insulin.	CV events (CV death, myocardial infarction, or stroke)	[45,51]
6.	Ipragliflozin	Suglat /(2S,3 R,4 R,5S,6 R)-2-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-6-(hydroxymethyl)oxane-3,4,5-triol	Astellas & Kotobuki Pharmaceuticals	10–15	UGT2B7	1–2% unchanged drug in feces	50 mg	1400	7.38	↓ in Hb1Ac and body weight fasting plasma glucose and ↑UGE, ↓ in SBP and DBP	hypoglycemic medications or diabetes medications	Polyuria, thirst, constipation, dehydration, and dizziness	[13,31,47,52]
7.	Tofogliflozin	Apleway or Deberza /(3S,3ʹR,4ʹS,5ʹS,6ʹR)-5-[(4-ethyl phenyl)methyl]-6’-(hydroxymethyl)spiro[1 H-2-benzofuran-3,2’-oxane]-3’,4’,5’-triol	Chugai Pharma & Sanofi	6 to 8	CYP2C18, 3A4/5, 4A11, and 4F3B	In feces	20–40 mg	8444	2.9	Reduction in Hb1Ac and body weight, ↓ in SBP, moderate hypoglycemia, ↑UTI	Sulfonylurea, metformin, DPP-4 inhibitors etc.	Polyuria, infections of urinary, genital, and upper respiratory tracts, thirst, skin disorders, increased constipation	[13,47,53–55]
8.	Luseogliflozin	Lusefi /(2S,3 R,4 R,5S,6 R)-2-[5-[(4-ethoxyphenyl)methyl]-2-methoxy-4-methylphenyl]-6-(hydroxymethyl)thiane-3,4,5-triol	Taisho Pharmaceutical Co.	9.2–13.8	1A1 (UGT1A1), CYP3A4,	In feces	2.5 or 5 mg	2900	2.29	↓ in HbA1c and fasting plasma glucose levels	sulfonylurea, metformin, etc.	urinary tract infection, renal impairment, genital infections	[40,47,56]
9.	Sotagliflozin	LX‐4211 /(2S,3 R,4 R,5S,6 R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyloxane-3,4,5-triol	Lexon and Sanofi Pharmaceuticals	2.5–4 h	UGT1A9,M19	In feces	200 mg	36	1.8	↓ BP and body weight controls glucose level in plasma.	Metformin and ddp4 inhibitors	Diabetic ketoacidosis, diarrhea, and genital infection	[41,47,57,58]

Figure 2. Chemical structures of different phlorizin-derived synthetic SGLT-2 inhibitors as antidiabetic in T2DM.

Table 2. List of Natural active Constituents investigated for antidiabetic action through SGLT2 inhibition.

S.no	Plant Name	Family	Active Constituents with SGLT inhibition	Extract	IC50 (in nm)		% inhibition		Ref
					SGLT1	SGLT2	SGLT1	SGLT2
1	Sophora flavescens	Fabaceae	Sophoraflavanone G, Kurarinone	Methanol	18.7 10.4	4.1 1.7	99.2 98.8	100 99.7	[61]
2.	Acer nikoense	Aceraceae	Acerogenins A Acerogenins B	Methanol	20.0 26.0	94.0 43.0	92.7 94.2	33.9 54.2	[72]
3.	Alstonia macrophylla	Apocynaceae	Alstiphyllanines D 17-O-Veratrate 10-methoxy-N-methylburnamie	Methanol	20.0 5.0 4.0	7.0 2.0 0.5	46.9 89.9 95.8	95.6 101.4 102.6	[67]
4.	Gnetum gnemonoides	Gnetaceae	Gneyulins A Gneyulins B	Acetone/H2O	27	25	MI	MI	[64]
5.	Schisandrae Chinensis Fructus	Schinsandraceae	Fraction 8	Ethanol or aqueous extract	–	–	–	42	[71]

MI = Moderate inhibition

Markham A. Remogliflozin Etabonate: first Global Approval. Drugs. 2019;79(10):1157–1161.

 PubMed Web of Science ®Google Scholar

Mohan V, Mithal A, Joshi SR, et al. Remogliflozin etabonate in the treatment of type 2 diabetes: design, development, and place in therapy. Drug Des Devel Ther. 2020;14:2487–2501.

 PubMed Web of Science ®Google Scholar

Beitelshees AL, Leslie BR, Taylor SI. Sodium–glucose cotransporter 2 inhibitors: a case study in translational research. Diabetes. 2019;68(6):1109–1120.

 PubMed Web of Science ®Google Scholar

Frampton JE. Empagliflozin: a Review in Type 2 Diabetes. Drugs. 2018;78(10):1037–1048.

 PubMed Web of Science ®Google Scholar

Kshirsagar RP, Kulkarni AA, Chouthe RS, et al. SGLT inhibitors as antidiabetic agents: a comprehensive review. RSC Adv. 2020;10(3):1733–1756.

 PubMed Web of Science ®Google Scholar

Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors A journal of Pharamacology and Therapeutics . 2012;14(1):83–90 doi:10.1111/j.1463-1326.2011.01517.x.

 Google Scholar

Fediuk DJ, Nucci G, Dawra VK, et al. Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor. Clin Pharmacokinet. 2020;59(8):949–965.

 PubMed Web of Science ®Google Scholar

Moradi-Marjaneh R, Paseban M, Sahebkar A. Natural products with SGLT2 inhibitory activity: possibilities of application for the treatment of diabetes. Phytother Res. 2019;33(10):2518–2530.

 PubMed Web of Science ®Google Scholar

Alkabbani W, Gamble JM. Profile of ipragliflozin, an oral sglt-2 inhibitor for the treatment of type 2 diabetes: the evidence to date. Drug Des Devel Ther. 2021;15:3057–3069.

 PubMed Web of Science ®Google Scholar

Tahara A, Kurosaki E, Yokono M, et al. Pharmacological profile of ipragliflozin (ASP1941), a novel selective SGLT2 inhibitor, in vitro and in vivo. Naunyn-Schmiedeberg’s Arch Pharmacol. 2012;385(4):423–436.

 Google Scholar

Samukawa Y, Sata M, Furihata K, et al. Luseogliflozin, an SGLT2 Inhibitor, in Japanese Patients With Mild/Moderate Hepatic Impairment: a Pharmacokinetic Study. Clin Pharmacol Drug Dev. 2017;6(5):439–447.

 PubMed Web of Science ®Google Scholar

Markham A, Elkinson S. Luseogliflozin: first global approval. Drugs. 2014;74(8):945–950.

 PubMed Web of Science ®Google Scholar

Markham A, Keam SJ. Sotagliflozin: first Global Approval. Drugs. 2019;79(9):1023–1029.

 PubMed Web of Science ®Google Scholar

Rosenstock J, Cefalu WT, Lapuerta P, et al. Greater dose-ranging effects on A1C levels than on glucosuria with lx4211, a dual inhibitor of SGLT1 and SGLT2, in patients with type 2 diabetes on metformin monotherapy. Diabetes Care. 2015;38(3):431–438.

 PubMed Web of Science ®Google Scholar

Zambrowicz B, Freiman J, Brown PM, et al. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a Randomized, placebo-controlled trial. Clin Pharmacol Ther. 2012;92(2):158–169.

 PubMed Web of Science ®Google Scholar

Sato S, Takeo J, Aoyama C, et al. Na+-Glucose cotransporter (SGLT) inhibitory flavonoids from the roots of Sophora flavescens. Bioorg Med Chem. 2007;15(10):3445–3449.

 PubMed Web of Science ®Google Scholar

Morita H, Deguchi J, Motegi Y, et al. Cyclic diarylheptanoids as Na+-glucose cotransporter (SGLT) inhibitors from Acer nikoense. Bioorganic Med Chem Lett. 2010;20(3):1070–1074.

 PubMed Web of Science ®Google Scholar

Arai H, Hirasawa Y, Rahman A, et al. Alstiphyllanines E-H, picraline and ajmaline-type alkaloids from Alstonia macrophylla inhibiting sodium glucose cotransporter. Bioorg Med Chem. 2010;18(6):2152–2158.

 PubMed Web of Science ®Google Scholar

Shimokawa Y, Akao Y, Hirasawa Y, et al. Gneyulins A and B, Stilbene Trimers, and Noidesols A and B, Dihydroflavonol- C -Glucosides, from the Bark of Gnetum gnemonoides. J Nat Prod. 2010;73(4):763–767.

 PubMed Web of Science ®Google Scholar

Qu Y, Chan JY-W, Wong C-W, et al. Antidiabetic Effect of Schisandrae Chinensis Fructus Involves Inhibition of the Sodium Glucose Cotransporter. Drug Dev Res. 2015;76(1):1–8.

 PubMed Web of Science ®Google Scholar