Renal selective N‐acetyl‐γ‐glutamyl prodrugs: a study on the mechanism of activation of the renal vasodilator prodrug CGP 22979

Drieman, J.C.; Thijssen, H. H. W.; Zeegers, H.H.M.; Smits, J. F. M.; Boudier, H. A. J. Struyker

doi:10.1111/j.1476-5381.1990.tb14646.x

Cited by 13 publications

(6 citation statements)

References 16 publications

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“…The N -acetyl group approach was chosen for fine-tuning the stability and prolonging the biological half-lives of our compounds. Several previous publications have demonstrated that the kidney is highly active in the accumulation and metabolism of N -acetyl-γ-glutamyl derivatives of drugs − showing a significantly increased kidney/liver distribution. This property was attributed to the high concentration of γ-GT, a specific and not completely identified transporter in the kidney, and the intracellular N -acylamine acid deacylase (ACY1) and γ-glutamylcyclotransferase, , altogether able to hydrolyze N -acetyl-γ-glutamyl derivatives of prodrugs, thus releasing the free drugs.…”

Section: Resultsmentioning

confidence: 99%

Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases

et al. 2015

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Notch is a membrane inserted protein activated by the membrane-inserted γ-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we have developed the γ-secretase inhibitor-based prodrugs 13a and 15a as substrates for γ-glutamyltranspeptidase (γ-GT) and/or γ-glutamylcyclotransferase (γ-GCT) as well as aminopeptidase A (APA), which are overexpressed in renal diseases, and have evaluated them in experimental in vitro and in vivo models. In nondiseased mice, the cleavage product from Ac-γ-Glu-γ-secretase inhibitor prodrug 13a (γ-GT-targeting and γ-GCT-targeting) but not from Ac-α-Glu-γ-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the γ-secretase inhibitor targeted prodrugs were investigated in vivo in a mouse model of acute kidney injury, demonstrating that the expression of Notch1 and cleaved Notch1 could be selectively down-regulated upon treatment with the Ac-γ-Glu-γ-secretase-inhibitor 13a.

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Section: Resultsmentioning

confidence: 99%

Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases

et al. 2015

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“…43 A physiological connection between afferent arteriolar diameter and adult blood pressure thus appears likely, a conclusion supported by the finding that specific renal artery dilators cause marked blood pressure reduction. 44 Furthermore, as mentioned above, prospective renal transplantation experiments in rats and retrospective studies of renal transplantations in humans point to a key role for the kidney in the etiology of hypertension. The present results are therefore consistent with the possibility that lumeny^ is a phenotype that determines blood pressure in SHR.…”

Section: Physiological Role For Afferent Arteriolar Diametermentioning

confidence: 96%

Early narrowed afferent arteriole is a contributor to the development of hypertension.

et al. 1994

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The kidney is probably critically involved in the development of essential hypertension, as in many genetic models of hypertension. We have investigated whether a narrowed renal afferent arteriole is involved in the pathogenesis of hypertension in spontaneously hypertensive rats. Systolic blood pressure of 37 F 2 generation spontaneously hypertensive rats/Wistar-Kyoto rats was measured at age 7 weeks. The right kidney was removed, and lumen diameter and media cross-sectional area of the afferent arterioles were measured after having been fixed while relaxed and under a transmural pressure of 100 mm Hg. The uninephrectomized rats continued until age 23 weeks, when mean blood pressure was measured. Mean blood pressure at 23 weeks was negatively A increasing amount of evidence supports a critical role for the kidney in the pathogenesis of essential hypertension.15 Key early observations concerned retrospective studies indicating that after kidney transplantation the blood pressure of recipients appeared to correlate with the blood pressure of donors. 68 More recently, the introduction of cyclosporine treatment with its own hypertensive effect has made it difficult to determine whether the blood pressure of donors influences the subsequent blood pressure of recipients. On the other hand, animal studies offer a means of examining this question in detail, 2 -3 and indeed, such studies have provided further strong evidence in support of the kidney playing a primary role in the development of genetic hypertension.Renal cross-transplantation experiments between inbred genetically hypertensive and normotensive rat strains show that kidneys taken from hypertensive donors cause the development of hypertension when transplanted to normotensive recipients.911 This is also the case if the donor rat has been kept normotensive with antihypertensive treatment until transplantation is performed, 11 suggesting that the renal effects are not secondary to hypertension-induced lesions but that a primary defect that can cause the blood pressure to increase may reside in the kidney. Received February 7, 1994; accepted in revised form May 26, 1994.From the Danish Biomembrane Research Centre and Department of Pharmacology, Aarhus University (Denmark), and Department of Medicine, University of Leicester (UK).Correspondence to Dr Niels Korsgaard, Department of Pharmacology, Aarhus University, University Park 240,8000 Aarhus C, Denmark.O 1994 American Heart Association, Inc.correlated with lumen diameter at 7 weeks. Quartile analysis based on lumen diameter at 7 weeks showed that compared with rats in the top lumen diameter quartile, rats in the bottom lumen diameter quartile had a reduced media cross-sectional area at 7 weeks (17%), the same systolic blood pressure at 7 weeks, and an increased (16%) mean blood pressure at 23 weeks. We conclude that in spontaneously hypertensive rats a narrowed lumen of distal afferent arterioles at 7 weeks contributes to later development of increased blood pressure. This reduced lumen could be c...

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“…As PRA was not increased, the effects are ascribed to the renal vasodilating properties of CGP 22979 (59). The mechanism behind the renal targeting via N-acetyl-y-L-glutamyl prodrugs was investigated in some detail in rats (35,36). The essential finding of these studies was that the renal selectivity was not due to activation by renal y-glutamyl transpeptidase but primarily due to selective uptake of the N-acetyl-y-L-glutamyl prodrug by tubular cells.…”

Section: Nhcochmentioning

confidence: 99%