| Diabetes mellitus is a metabolic disease about glucose, protein and adipose, which can lead to the rise of plasma glucose level. Due to the progressive essence of the disease, untreated hyperglycemia causes the damages of tissues which can result in many complications about micro-and macro-vascular lesions including retinopathy, nephropathy, and neuropathy, as well as stroke and coronary artery disease. It inhibits wound healing as well which accelerates infections and gangrene of lower limb. Long-term hyperglycemia induces oral health problems and sleep apnea. Persistent high plasma glucose levels speed up insulin resistance but also advance beta-cell apoptosis. With the development of living standard and changes of life-style, diabetes mellitus becomes more and more alarming worldwide.Diabetes mellitus is mainly composed of two common forms including type2diabetes mellitus and type1diabetes mellitus. Type1diabetes mellitus also known as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune breakdown of pancreatic β-cell, and thus bring about the reduction or vanishing of organismal insulin production. Type2diabetes mellitus also known as non-insulin-dependent diabetes mellitus (NIDDM), is featured by the loss of sensitive tissues to reply to insulin (insulin resistance) and by the beta-cell disfunction causing high concentration of blood sugar. T2DM accounts for90-95%among all the clinical diagnosis patients. What’s more, these current antidiabetic drugs have side effects in different degree, such as weight gain, hypoglycemic, water retention and gastrointestinal side effects (naupathia and vomit). Traditional antidiabetic medications mostly focus on exploiting these drugs which boost endogenous insulin secretion and/or elevate insulin sensitivity. The progressive nature of diabetes determines single therapy and/or combination therapy unsatisfied with the whole process control of diabetes mellitus. Not all patients with DM can achieve targeted glycemic control levels (HbA1c□7.0%) according to the United Kingdom Prospective Diabetes Study (UKPDS). Thus well-tolerated novel drugs with patent mechanisms of action are required at every phase of the disease to regulate glucose level.The kidney reabsorbs plasma glucose when it is filtered in the glomerulus. Thus, the kidney plays a very important role in glucose homeostasis. Hyperglycemia is the quality of T2MD. We can develop a kind of drug that has the ability to inhibit/stop the reabsorption of glucose to achieve the goal of lowering plasma glucose. This mechanism of action is other than traditional antidiabetic drugs above-mentioned. As we know, glucose taked in human body largely is absorbed in small intestinal aided by SGLT1, and residual glucose is filtered in the glomerulus when it arrives in the kidney. The residue is reabsorbed in the proximal tubules (PT). The reabsorption process is mediated by two SGLTs, SGLT2and SGLT1included. More than90%glucose returns to the blood circle activated by SGLT2in S1segment of the PCT, and less than10%glucose aided by SGLT1. Therefore, we can design and synthesize novel compounds used for inhibiting the reabsorption of renal glucose to attain plasma glucose levels. And thus SGLT2inhibitors are becoming more and more attractive for chemists and pharmacologists.This paper is based on the current situation about antidiabetics globally, analyzing the structures of SGLT2inhibitors marketed or under different clinical stages, and come to a conclusion that almost all SGLT2inhibitors chose dapagliflozin as lead-compound. Canagliflozin, ipragliflozin and empagliflozin were synthesized by modifications of aglycon in lead-compound dapagliflozin while holding the sugar moiety invariant. LX4211and PF-04971729were synthesized by modifications of moiety in dapagliflozin while holding aglycon invariant. The obtainments of tofogliflozin and TS-071rooted in the modifications of the lead compound dapagliflozin, the aglycon and the sugar moiety included. These modifications of dapagliflozin abided by the rules that polarity of sugar moieties and aromaticity and lipophilicity of aglycons. In other words, the appropriate polarity and aromaticity coming from SGLT2inhibitors can maintain biological activity.The starting point of aforementioned three kinds of SGLT2inhibitors were designed and synthesized rooting in modifications of dapagliflozin. However, no one elaborated four hydroxyl groups of the sugar moiety on SARs.This paper chose dapagliflozin as the lead compound and deoxidized four hydroxyl groups solely in turn and deoxidized four hydroxyl groups in couples respectively (see Fig.l). The products included D6(6-deoxydapagliflozin), D4(4-deoxydapagliflozin), D3(3-deoxydapagliflozin) and D2(2-deoxydapagliflozin). The in vitro assays of D6, D4, D3and D2against hSGLT2and hSGLTl were performed according to the reported procedure. The results of in vitro assays told us the structure-activity relationships (SRAs) of the four hydroxyl groups in the sugar moiety of dapagliflozin.D6(6-deoxydapagliflozin) was found to be a significantly more active SGLT2inhibitor (IC50=0.67nM vs1.16nM), which demonstrated that6-OH is completely unnecessary for SGLT2inhibitory activity and the existence of6-OH lowers SGLT2 inhibitory in some degree.D4(4-deoxydapagliflozin) was less active against hSGLT2by one order of magnitude than parent compound dapagliflozin (IC50=12.8nM vs1.16nM), indicating that4-OH is also vital to SGLT2inhibition.D3(3-deoxydapagliflozin) exhibited a little bit lower hSGLT2inhibitory activity (IC50=1.5nM vs1.16nM) but slightly higher hSGLT2/hSGLTl selectivity (986vs823) as compared with dapagliflozin, which made D3basically comparable with dapagliflozin, indicating that3-OH is unnecessary for both SGLT2inhibition and hSGLT2/hSGLT1selectivity.D2(2-deoxydapagliflozin) was almost completely inactive against hSGLT2(IC50=8,345nM), indicating that2-OH is indispensable for SGLT2inhibition.The outcomes coming from the assays in vitro of D6, D4, D3and D2attracted the next di-deoxydapagliflozin derivatives. According to the aforementioned outcomes, we chose D36(3,6-dideoxydapagliflozin) as targeted molecular compound.The assay of D36in vitro elaborated that3-OH and6-OH were deoxidized simultaneously, resulting in SGLT2inhibitory of the product vanishing completely. In other words, the deoxylations of6-OH and3-OH of the lead compound changed polarity and aromaticity completely. The affinity between acceptor (SGLT2) with D36(3,6-dideoxydapagliflozin) became very week so that the SGLT2ability of the D36(3,6-dideoxydapagliflozin) disappeared thoroughly. Only the numbers of hydroxyl groups in the sugar moiety of dapagliflozin not less than three could the SGLT2inhibitory be sustained.Systematic mono-deoxylation and di-deoxylation of the four hydroxyl groups in the glucose moiety of the lead compound dapagliflozin lea to the discovery of D6as a more potent SGLT2inhibitor (IC50=0.67nM against hSGLT2vs1.16nM for dapagliflozin). It exhibited more effective blood glucose inhibitory activity in rat OGTT and could induce more urinary glucose in rat urinary glucose excretion (UGE) test than its parent compound dapagliflozin. This finding demonstrates that the6-OH in the moiety of dapagliflozin lowers the affinity between itself with the protein SGLT2. It could be a more potent SGLT2inhibitor without the6-OH group in the moiety of dapagliflozin. Thus6-deoxylation can be well tolerated; however,6-deoxylation can lead to a slight decrease in terms of SGLT2/SGLT1selectivity, which was still high enough in the field of druggability. |
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