Structure–activity relationship studies of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia

Fushimi, Nobuhiko; Fujikura, Hideki; Shiohara, Hiroaki; Teranishi, Hirotaka; Shimizu, Kazuo; Yonekubo, Shigeru; Ohno, Kohsuke; Miyagi, Takashi; Itoh, Fumiaki; Shibazaki, Toshihide; Tomae, Masaki; Ishikawa-Takemura, Yukiko; Nakabayashi, Takeshi; Kamada, Noboru; Ozawa, Tomonaga; Kobayashi, Susumu; Isaji, Masayuki

doi:10.1016/j.bmc.2012.09.037

Cited by 18 publications

(17 citation statements)

References 37 publications

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“…A series of 4-benzyl-1 H -pyrazol-3-yl β- d -glucopyranoside derivatives were synthesized and evaluated for their inhibitory activity toward sodium glucose co-transporter 1 (SGLTs). Compound 447 was identified as potent and selective SGLT1 inhibitors, both of which showed improved in vitro intestinal stability over phlorizin, high solubility to water [ 344 ].…”

Section: Pharmacological Activitiesmentioning

confidence: 99%

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

et al. 2018

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Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.

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Section: Pharmacological Activitiesmentioning

confidence: 99%

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

et al. 2018

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“…The use of these compounds provided first insights on the potential efficacy of SGLT1 inhibition on glucose homeostasis as well as the safety of such an approach, as discussed in the following. Other studies also indicated the feasibility to develop molecules that inhibit SGLT1 but not SGLT2 [144, 149, 150]. The development of selective SGLT1 inhibitors needs to consider the potential metabolism to aglycone-derivatives and their potential effects on different epithelial transport mechanisms (e.g., see the below discussed conversion of phlorizin to its aglycone, phloretin).…”

Section: Therapeutic Potential Of Sglt1 Inhibitionmentioning

confidence: 99%

Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

Song

Ōnishi

Koepsell

et al. 2016

Expert Opinion on Therapeutic Targets

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Introduction Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium–glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential. Areas covered This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes. The therapeutic potential of SGLT1 inhibition, alone as well as in combination with SGLT2 inhibition, for anti-hyperglycemic therapy are discussed. Additionally, this review considers the effects on other SGLT1-expressing organs like the heart. Expert opinion SGLT1 inhibition improves glucose homeostasis by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased in diabetes and during inhibition of SGLT2, which deliver more glucose to SGLT1 in late proximal tubule. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe. More data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition.

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“…The pyrazole moiety is commonly found in several pharmaceuticals and agrochemicals [1]. In particular, hydroxy-pyrazole units are described as antiviral (HIV-1 non-nucleoside reverse transcriptase inhibitors, 1) [2], anti-diabetic (Na-glucose cotransporter inhibitors, 3) [3][4][5], anti-cancer (Hsp90 inhibitor, 2) [6], anti-thrombotic (P2Y 1 antagonist 4) [7], and antibacterial agents (5) [8,9] (examples in Figure 1). The 3-hydroxy-2-oxindole moiety is another related and widely represented motif present in several natural products (9,10,12) [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%