Discovery of Tofogliflozin, a Novel <i>C</i>-Arylglucoside with an <i>O</i>-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Ohtake, Yoshihito; Sato, Tsutomu; Kobayashi, Takamitsu; Nishimoto, Mamoru; Taka, Naoki; Takano, Koji; Yamamoto, Keisuke; Ohmori, Masayuki; Yamaguchi, Marina; Takami, Kyoko; Yeu, Sang-Yong; Ahn, Koo-Hyeon; Matsuoka, Hirotaka; Morikawa, Kazuo; Suzuki, Masayuki; Hagita, Hitoshi; Ozawa, Kazuharu; Yamaguchi, Koji; Kato, Motohiro; Ikeda, Sachiya

doi:10.1021/jm300884k

Cited by 145 publications

(81 citation statements)

References 46 publications

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“…Novel inhibitors for many transporters have been identified through these methods, including inhibitors of apical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) 55, 56 , excitatory amino acid transporter 3 (EAAT3; also known as SLC1A1) 57 , dopamine transporter (DAT; also known as SLC6A3), serotonin transporter (SERT; also known as SLC6A4), noradrenaline transporter (NET; also known as SLC6A2) 58, 59, 60 and vesicular glutamate transporter 2 (VGLUT2; also known as SLC17A6) 61 . For example, the O -spiroketal C-arylglucoside scaffold — which forms the basis of tofogliflozin (Apleway/Deberza; Chugai Pharmaceutical/Sanofi/Kowa, a selective sodium–glucose cotransporter 2 (SGLT2; also known as SLC5A2) inhibitor recently approved in Japan for the treatment of diabetes — was found by pharmacophore modelling of SGLT2 inhibitors and a search of the Cambridge Structural Database 62 (see Databases).…”

Section: Strategies For Targeting Slc Transportersmentioning

confidence: 99%

SLC transporters as therapeutic targets: emerging opportunities

Lin

Yee

Kim

et al. 2015

Nat Rev Drug Discov

655

552

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Solute carrier (SLC) transporters — a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes — have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.

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Section: Strategies For Targeting Slc Transportersmentioning

confidence: 99%

SLC transporters as therapeutic targets: emerging opportunities

Lin

Yee

Kim

et al. 2015

Nat Rev Drug Discov

655

552

View full text Add to dashboard Cite

show abstract

“…2, 4-6 These approaches have been used to develop ligands for transporters such as the Apical Sodium Dependent Bile Acid Transporter (ASBT/SLC10A2) 7 and Multidrug and Toxin Extrusion Transporter 1 (MATE1, SLC47A1), 8 as well as to guide the discovery of tofogliflozin, an SGLT2 (SLC5A2) ligand currently prescribed to treat type-2 diabetes in Japan. 9 However, ligand-based methods are limited in their ability to capture molecules that are chemically distinct from known ligands and to describe the molecular interactions between the transporter and its ligand. Conversely, computational approaches that rely on three-dimensional structures of proteins can be useful for identifying novel chemical scaffolds with virtual screening of large compound libraries, 10 or optimizing lead compounds or known drugs with methods such as Molecular Dynamics (MD) simulations and free energy calculations.…”

Section: Slc Structurementioning

confidence: 99%

SLC transporters: structure, function, and drug discovery

2016

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The human Solute Carrier (SLC) transporters are important targets for drug development. Structure-based drug discovery for SLC transporters requires the description of their structure, dynamics, and mechanism of interaction with small molecule ligands and ions. The recent determination of atomic structures of human SLC transporters and their homologs, combined with improved computational power and prediction methods have led to an increased applicability of structure-based drug design methods for human SLC members. In this review, we provide an overview of the SLC transporters’ structures and transport mechanisms. We then describe computational techniques, such as homology modeling and virtual screening that are emerging as key tools to discover chemical probes for human SLC members. We illustrate the utility of these methods by presenting case studies in which rational integration of computation and experiment was used to characterize SLC members that transport key nutrients and metabolites, including the amino acid transporters LAT-1 and ASCT2, the SLC13 family of citric acid cycle intermediate transporters, and the glucose transporter GLUT1. We conclude with a brief discussion about future directions in structure-based drug discovery for the human SLC superfamily, one of the most structurally and functionally diverse protein families in human.

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“…15), including dapagliflozin ( 56 ) 26 , empagliflozin ( 57 ) 27 , and ipragliflozin ( 58 ) 28 in 2014, and tofogliflozin ( 59 ) 29 is in the phase III clinical trials.…”

Section: Examples Of Successful Modificationsmentioning

confidence: 99%

The modification of natural products for medical use

Guo

2017

Acta Pharmaceutica Sinica B

260

156

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Drug innovation is characterized by painstaking molecular-level syntheses and modifications as the basic components of research and development. Similarly, natural products are chemically tailored and modified based upon their structural and biological properties. To some extent, the modification of natural products is quite different from de novo structure-based drug discovery. This review describes the general strategies and principles for the modification of natural products to drugs, as illustrated by several successful medicines that originated from natural products.

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Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Cited by 145 publications

References 46 publications

SLC transporters as therapeutic targets: emerging opportunities

SLC transporters as therapeutic targets: emerging opportunities

SLC transporters: structure, function, and drug discovery

The modification of natural products for medical use

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