[(S)-γ-(Arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors

Sakashita, Hiroshi; Akahoshi, Fumihiko; Kitajima, Hiroshi; Tsutsumiuchi, Reiko; Hayashi, Yoshiharu

doi:10.1016/j.bmc.2006.01.022

Cited by 29 publications

(5 citation statements)

References 16 publications

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“…Covalent and noncovalent inhibitors of DPP IV have been designed, developed, and evaluated in vitro, in vivo, and in clinical trials. Several synthetic routes were explored during these initial developments, − which will not be described in depth in this Perspective. We and many others have recently reviewed these initial developments. ,,, Thus, only the most relevant information, and in particular the information concerning the molecules that were evaluated in humans, will be provided here.…”

Section: Initial Development Of Dpp IV Inhibitors In Clinical Use For...mentioning

confidence: 99%

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: Initial Development Of Dpp IV Inhibitors In Clinical Use For...mentioning

confidence: 99%

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

2013

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“…However, the cocktail of inhibitors used in the present study is unlikely to be used for clinical management because of the likelihood of side effects from some, or all, of the components in such mixtures. For this reason, other strategies must be explored to reach the same goal of increasing the stability and half-life of therapeutic peptides. ,− For example, fusing a peptide to the stable bacterial Rop (repressor of primer) protein or incorporation of two proline residues has been shown to significantly increase resistance to proteinase-induced degradation . Conjugating alpha1 proteinase inhibitor (α1PI) with poly(ethylene glycol) (PEG) at Cys (232) has also been observed to extend the in vivo half-life of α1PI in the bloodstream .…”

Section: Discussionmentioning

confidence: 99%

Degradation of the α-Carboxyl Terminus 11 Peptide: In Vivo and Ex Vivo Impacts of Time, Temperature, Inhibitors, and Gender in Rat

Tasdemiroglu,

Council-Troche,

Chen

et al. 2024

ACS Pharmacol. Transl. Sci.

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In previous research, a synthetic α-carboxyl terminus 1 (αCT1) peptide derived from connexin 43 (Cx43) and its variant (αCT11) showed beneficial effects in an ex vivo ischemia−reperfusion (I/R) heart injury model in mouse. In an in vivo mouse model of cryo-induced ventricular injury, αCT1 released from adhesive cardiac patches reduced Cx43 remodeling and arrhythmias, as well as maintained cardiac conduction. Whether intravenous injection of αCT1 or αCT11 produces similar outcomes has not been investigated. Given the possibility of peptide degradation in plasma, this study utilized in vivo I/R cardiac injury and ex vivo blood plasma models to examine factors that may limit the therapeutic potential of peptide therapeutics in vivo. Following tail vein administration of αCT11 (100 μM) in blood, no effect on I/R infarct size was observed in adult rat hearts on day 1 (D1) and day 28 (D28) after injury (p > 0.05). There was also no difference in the echocardiographic ejection fraction (EF %) between the control and the αCT11 groups (p > 0.05). Surprisingly, αCT11 in blood plasma collected from these rats was undetectable within ∼10 min after tail vein injection. To investigate factors that may modulate αCT11 degradation in blood, αCT11 was directly added to blood plasma isolated from normal rats without I/R and peptide levels were measured under different experimental conditions. Consistent with in vivo observations, significant αCT11 degradation occurred in plasma within 10 min at 22 and 37 °C and was nearly undetectable by 30 min. These responses were reduced by the addition of protease/phosphatase (PTase/ PPTase) inhibitors to the isolated plasma. Interestingly, no significant differences in αCT11 degradation in plasma were noted between male and female rats. We conclude that fast degradation of αCT11 is likely the reason that no beneficial effects were observed in the in vivo I/R model and inhibition or shielding from PTase/PPTase activity may be a strategy that will assist with the viability of peptide therapeutics.

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“…是一类丝氨酸蛋白酶 [1] ，能快速地降解胰高血糖素样肽 1(GLP-1，glucagon-like peptide-1)。而 GLP-1 能够促进胰岛素的合成和分泌，降低餐后血糖 [2] 。抑制 DPP-Ⅳ能增强内源性 GLP-l 的作用，从而提高血液中胰岛素的水平，降低糖尿病人的血糖水平 [3] 。因此 DPP-Ⅳ抑制剂被认为是一种新型的抗糖尿病治疗药物 [4] 。2006 年默克公司的抗糖尿病治疗药物西他列汀…”

Section: Dpp-ⅳ抑制剂三维药效团模型构建 *unclassified

3D Pharmacophore Model Construction of DPP-Ⅳ Inhibitors

韩天佼¹,

李悦青²,

谷俊峰³

et al. 2012

HJCET

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The 3D pharmacophore model of DPP-Ⅳ inhibitors was established using the Discovery Studio software with the training set of 20 DPP-Ⅳ inhibitors. The best pharmacophore hypothesis (Hypo 1) consists of one hydrogen-bond acceptor, one hydrophobic point, one positive ionizable group, one aromatic ring as well as five excluded volumes. Fischer's validation clearly shows that proposed Hypo 1 has highly predictive ability and can be efficiently used as a 3D query for virtual screening to retrieve potential inhibitors from ZINC databases. The hit compounds subsequently were docked into the DPP-Ⅳ active site and 21 compounds were obtained based on PLP2 scoring function. Therefore, this study could provide scientific basis for denovo design of DPP-Ⅳ inhibitors.

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[(S)-γ-(Arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors

Cited by 29 publications

References 16 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?

Degradation of the α-Carboxyl Terminus 11 Peptide: In Vivo and Ex Vivo Impacts of Time, Temperature, Inhibitors, and Gender in Rat

3D Pharmacophore Model Construction of DPP-Ⅳ Inhibitors

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