Synthesis and pharmacological characterization of potent, selective, and orally bioavailable isoindoline class dipeptidyl peptidase IV inhibitors

Kato, Nanako; Oka, Mitsuru; Murase, Takayo; Yoshida, Masahiro; Sakairi, Masao; Mirensha, Yakufu; Yamashita, Satoko; Yasuda, Yoshika; Yoshikawa, Aya; Hayashi, Yuji; Shirai, Masahiro; Mizuno, Yukie; Takeuchi, Miki; Makino, Mitsuhiro; Takeda, Motohiro; Kakigami, Takuji

doi:10.1186/2191-2858-1-7

Cited by 20 publications

(10 citation statements)

References 12 publications

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“…93 Small modifications of already approved molecules were also explored; for example, from the β-aminoamide backbone of compound 4, compound 25 was proposed. 94 Isoindoline-based 85 and pyrrolopyrimidine-based 95 The most recent developments of improved small molecule DPP IV inhibitors relied on computing approaches. By use of such tools and chemical refinement of the lead structure 21, compound 22 (TAK-100) was developed, 62,90,96 the first in its class to bear a carboxyl group to reach clinical trial, presently in phase 1.…”

Section: ■ More Recent Dpp IV Inhibitors Under Developmentmentioning

confidence: 99%

“…Several excellent recent reviews have been published covering the development of potential new therapeutic DPP IV inhibitors; ,, thus, only the most relevant findings will be discussed in this Perspective and only the very recent publications, covering 2011 to early 2013, will be discussed here in more detail. Several new molecules have reached different phases of clinical trials (Table ), including for example 14 (anagliptin/SK-0403), , 18 (DA-1229), 19 (E3024), 20 ( TAK-100), or the long-lasting compounds 10 (omarigliptin/MK-3102 , (Table ) and PKF-275-055 (structure not disclosed), or are in preclinical evaluation (Scheme ).…”

Section: More Recent Dpp IV Inhibitors Under Developmentmentioning

confidence: 99%

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Dipeptidyl Peptidase IV and Its Inhibitors: Therapeutics for Type 2 Diabetes and What Else?

2013

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The proline-specific dipeptidyl aminopeptidase IV (DPP IV, DPP-4, CD26), widely expressed in mammalians, releases X-Pro/Ala dipeptides from the N-terminus of peptides. DPP IV is responsible of the degradation of the incretin peptide hormones regulating blood glucose levels. Several families of DPP IV inhibitors have been synthesized and evaluated. Their positive effects on the degradation of the incretins and the control of blood glucose levels have been demonstrated in biological models and in clinical trials. Presently, several DPP IV inhibitors, the "gliptins", are approved for type 2 diabetes or are under clinical evaluation. However, the gliptins may also be of therapeutic interest for other diseases beyond the inhibition of incretin degradation. In this Perspective, the biological functions and potential substrates of DPP IV enzymes are reviewed and the characteristics of the DPP IV inhibitors are discussed in view of type 2 diabetes and further therapeutic interest.

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Section: ■ More Recent Dpp IV Inhibitors Under Developmentmentioning

confidence: 99%

Section: More Recent Dpp IV Inhibitors Under Developmentmentioning

confidence: 99%

Dipeptidyl Peptidase IV and Its Inhibitors: Therapeutics for Type 2 Diabetes and What Else?

2013

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“…The example chosen was a DPPIV medicinal chemistry paper from European PubMed Central (PMC3305890) with free full text-access published by the company Kenkyusho in 2006 [18]. The question “how many structures could be extracted?” was answered as 52 from the PubMed Central URL.…”

Section: Resultsmentioning

confidence: 99%

Extracting and connecting chemical structures from text sources using chemicalize.org

Southan¹,

Stracz²

2013

J Cheminform

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BackgroundExploring bioactive chemistry requires navigating between structures and data from a variety of text-based sources. While PubChem currently includes approximately 16 million document-extracted structures (15 million from patents) the extent of public inter-document and document-to-database links is still well below any estimated total, especially for journal articles. A major expansion in access to text-entombed chemistry is enabled by chemicalize.org. This on-line resource can process IUPAC names, SMILES, InChI strings, CAS numbers and drug names from pasted text, PDFs or URLs to generate structures, calculate properties and launch searches. Here, we explore its utility for answering questions related to chemical structures in documents and where these overlap with database records. These aspects are illustrated using a common theme of Dipeptidyl Peptidase 4 (DPPIV) inhibitors.ResultsFull-text open URL sources facilitated the download of over 1400 structures from a DPPIV patent and the alignment of specific examples with IC50 data. Uploading the SMILES to PubChem revealed extensive linking to patents and papers, including prior submissions from chemicalize.org as submitting source. A DPPIV medicinal chemistry paper was completely extracted and structures were aligned to the activity results table, as well as linked to other documents via PubChem. In both cases, key structures with data were partitioned from common chemistry by dividing them into individual new PDFs for conversion. Over 500 structures were also extracted from a batch of PubMed abstracts related to DPPIV inhibition. The drug structures could be stepped through each text occurrence and included some converted MeSH-only IUPAC names not linked in PubChem. Performing set intersections proved effective for detecting compounds-in-common between documents and merged extractions.ConclusionThis work demonstrates the utility of chemicalize.org for the exploration of chemical structure connectivity between documents and databases, including structure searches in PubChem, InChIKey searches in Google and the chemicalize.org archive. It has the flexibility to extract text from any internal, external or Web source. It synergizes with other open tools and the application is undergoing continued development. It should thus facilitate progress in medicinal chemistry, chemical biology and other bioactive chemistry domains.

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“…Inhibition of plasma DPP-4 activity was determined by measuring the hydrolysis rate of a surrogate substrate, H-Gly-Pro-7-amino-4-methylcoumarin (H-Gly-Pro-AMC). The measurement procedure was previously described [ 32 ] . Briefl y, plasma samples were mixed with substrate solution.…”

Section: Measurement Of Dpp-4 Inhibition In Plasmamentioning

confidence: 99%

The Relationship between Anagliptin Concentration Showing Over 80% Inhibition of Plasma Dipeptidyl Peptidase-4 Activity and its Protective Effect against Glucagon-like Peptide-1 Degradation

Furuta¹,

Goto²,

Tamura³

et al. 2013

Drug Res (Stuttg)

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In dipeptidyl peptidase-4 (DPP-4) inhibitors, the inhibition of plasma DPP-4 activity by 80% is considered sufficient to have an effect on glycemic control improvement through the elevation of intact glucagon-like peptide-1 (GLP-1). To clarify whether or not the 80% inhibition is sufficient to protect against GLP-1 degradation, we investigated rats with a continuous infusion of exogenous GLP-1. When GLP-1 was infused into the femoral or portal vein, the steady state active GLP-1 levels in plasma significantly increased (P<0.05) at the 80% inhibitory concentration (IC80) of anagliptin (a highly selective DPP-4 inhibitor) against plasma DPP-4 activity, compared with control. In addition, the peptide levels increased in a concentration-dependent manner at drug concentrations from IC80 to 10-fold IC80, and the levels at the 10-fold IC80 were significantly higher (P<0.05) than those at IC80. The concentration dependency on GLP-1 increment was also confirmed based on the experiment in which the endogenous active GLP-1 levels were measured after an oral carbohydrate load. These findings suggest that an almost complete inhibition (80%) of plasma DPP-4 activity was insufficient to protect GLP-1 degradation, and much higher drug concentrations such as 10-fold IC80 are necessary to potently protect GLP-1 from degradation by DPP-4 commonly present in blood and tissues.

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Synthesis and pharmacological characterization of potent, selective, and orally bioavailable isoindoline class dipeptidyl peptidase IV inhibitors

Cited by 20 publications

References 12 publications

Dipeptidyl Peptidase IV and Its Inhibitors: Therapeutics for Type 2 Diabetes and What Else?

Dipeptidyl Peptidase IV and Its Inhibitors: Therapeutics for Type 2 Diabetes and What Else?

Extracting and connecting chemical structures from text sources using chemicalize.org

The Relationship between Anagliptin Concentration Showing Over 80% Inhibition of Plasma Dipeptidyl Peptidase-4 Activity and its Protective Effect against Glucagon-like Peptide-1 Degradation

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