Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): A highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

Yoshida, Tomohiro; Akahoshi, Fumihiko; Sakashita, Hiroshi; Kitajima, Hiroshi; Nakamura, Masashi; Sonda, Shuji; Takeuchi, Masahiro; Tanaka, Yoshihito; Ueda, Naoko; Sekiguchi, Sumie; Ishige, Takayuki; Shima, Kyoko; Nabeno, Mika; Abe, Yuji; Anabuki, Jun; Soejima, Aki; Yoshida, Kumiko; Takashina, Yoko; Ishii, Shin‐ichi; Kiuchi, Satoko; Fukuda, Saburo; Tsutsumiuchi, Reiko; Kosaka, Keigo; Murozono, Takahiro; Nakamaru, Yoshinobu; Utsumi, Hiroyuki; Masutomi, Naoya; Kishida, Hiroyuki; Miyaguchi, Ikuko; Hayashi, Yoshiharu

doi:10.1016/j.bmc.2012.08.012

Cited by 139 publications

(88 citation statements)

References 34 publications

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“…We concluded that the high selectivity of anagliptin was attributable to the utilization of the S 2 extensive site as in the cases of sitagliptin 31 and teneligliptin 29 . Further, the SAR study of anagliptin derivatives reasonably accounted for the influence of the substituent on the heterocycle, which interacted at the S 2 extensive site.…”

Section: Resultsmentioning

confidence: 87%

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Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions

Watanabe

Yasuda

Kojima

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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The single-crystal structure of anagliptin,-a]pyrimidine-6-carboxamide, was determined. Two independent molecules were held together by intermolecular hydrogen bonds, and the absolute configuration of the 2-cyanopyrrolidine ring delivered from L-prolinamide was confirmed to be S. The interactions of anagliptin with DPP-4 were clarified by the co-crystal structure solved at 2.85 Å resolution. Based on the structure determined by X-ray crystallography, the potency and selectivity of anagliptin were discussed, and an SAR study using anagliptin derivatives was performed.

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Section: Resultsmentioning

confidence: 87%

“…The S 2 extensive subsite contributes to the affinity and selectivity as described in the characterizations of sitagliptin 15 and teneligliptin 29 . The selectivity against DPP-4 homologues in Figure 2.…”

Section: Co-crystal Structure Of Dpp-4 With Anagliptinmentioning

confidence: 99%

Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions

Watanabe

Yasuda

Kojima

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…165 The thiazolidine moiety fully occupies the S 1 hydrophobic subsite; the secondary amino group of the proline moiety forms salt bridges with Glu205 and Glu206; the carbonyl oxygen forms a hydrogen bond with Asn710; and the pyrazolyl ring is stacked with the side chain of Phe357 and the piperazinyl ring forms CH-p interaction with Phe357. 165 In addition, the phenyl substituent on the pyrazolyl ring is oriented favourably for hydrophobic interactions with the side chains of Ser209 and Arg358. In the S 2 extensive subsite, C4 of the phenyl ring is highly possible to form hydrogen bond with the carbonyl oxygen of the main chain of Val207.…”

Section: Safety Of Sitagliptinmentioning

confidence: 99%

“…fatty rats significantly inhibited DPP-4 activity and normalized the plasma glucose levels after an oral glucose load of 1.0 g/kg. 165 An X-ray co-crystal structure of teneligliptin complexed with human DPP-4 (33-766; protein database ID: 3VJM) has demonstrated that there are tight interactions between five rings of teneligliptin and the active site of DPP-4. 165 The thiazolidine moiety fully occupies the S 1 hydrophobic subsite; the secondary amino group of the proline moiety forms salt bridges with Glu205 and Glu206; the carbonyl oxygen forms a hydrogen bond with Asn710; and the pyrazolyl ring is stacked with the side chain of Phe357 and the piperazinyl ring forms CH-p interaction with Phe357.…”

Section: Safety Of Sitagliptinmentioning

confidence: 99%

“…165 An X-ray co-crystal structure of teneligliptin complexed with human DPP-4 (33-766; protein database ID: 3VJM) has demonstrated that there are tight interactions between five rings of teneligliptin and the active site of DPP-4. 165 The thiazolidine moiety fully occupies the S 1 hydrophobic subsite; the secondary amino group of the proline moiety forms salt bridges with Glu205 and Glu206; the carbonyl oxygen forms a hydrogen bond with Asn710; and the pyrazolyl ring is stacked with the side chain of Phe357 and the piperazinyl ring forms CH-p interaction with Phe357. 165 In addition, the phenyl substituent on the pyrazolyl ring is oriented favourably for hydrophobic interactions with the side chains of Ser209 and Arg358.…”

Section: Safety Of Sitagliptinmentioning

confidence: 99%

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Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Chen

Zhou

et al. 2015

Clin Exp Pharma Physio

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SUMMARYDipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucoselowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.

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Dipeptidyl Peptidase 4 Inhibitors

Weber¹,

Thornberry²

2021

Burger's Medicinal Chemistry and Drug Discovery

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Type 2 diabetes (T2DM) is a growing worldwide epidemic. While a number of oral agents have been available to treat T2DM, they suffer from safety and tolerability issues and lack durability. In the 1990s, glucagon‐like peptide 1 (GLP‐1) emerged as a new approach to glucose lowering. Endogenous GLP‐1 is rapidly inactivated through the action of dipeptidyl peptidase 4 (DPP‐4), a serine dipeptidyl aminopeptidase that cleaves its N‐terminal two amino acids. Blocking DPP‐4 with a small molecule inhibitor was shown to increase circulating levels of GLP‐1 in rodent models and humans, leading to improved glucose control. Early DPP‐4 inhibitors were dipeptide mimetics, some of which bound to the DPP‐4 active site serine in a covalent manner. Screening and structure‐based drug design led to the identification of many other structural classes. In 2006, sitagliptin became the first DPP‐4 inhibitor approved by the FDA. Inhibitors now available include two for once‐weekly administration. Over 10 years of clinical experience has shown DPP‐4 inhibition to be safe and effective with a low risk of hypoglycemia, no weight gain, and no increased cardiovascular risk. Used as monotherapy or in combination with other glucose‐lowering medications, DPP‐4 inhibitors have become an important class of oral agents to treat T2DM.

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Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): A highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

Cited by 139 publications

References 34 publications

Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions

Anagliptin, a potent dipeptidyl peptidase IV inhibitor: its single-crystal structure and enzyme interactions

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Dipeptidyl Peptidase 4 Inhibitors

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