Synthesis and in vitro activities of new non‐peptidic APA Inhibitors

Inguimbert, Nicolas; Coric, Pascale; Dhôtel, Hélène; Bonnard, Elisabeth; Llorens-Cortes, Catherine; Mota, Nadia De; Fournié‐Zaluski, M. C.; Roques, Bernárd P.

doi:10.1111/j.1399-3011.2004.00211.x

Cited by 23 publications

(15 citation statements)

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“…Most of the applications are oriented to the design of inhibitors for specific aminopeptidases. Selective inhibitors of glutamyl aminopeptidase (aminopeptidase A) constitute potential antihypertensive agents due to the role of this enzyme in the conversion of angiotensin II into angiotensin III, which plays an essential role in control of arterial blood pressure (Cogolludo et al, 2005;Inguimbert et al, 2005). The design of inhibitors of methionine aminopeptidases is also considered to be of therapeutic potential due to the role of these enzymes in angiogenesis and tumour growth (Selvakumar et al, 2005;Zhong and Bowen, 2006).…”

Section: The Pharmaceutical Industrymentioning

confidence: 99%

“…Thus, these enzymes can efficiently retrieve amino acids from dietary proteins and endogenous proteins degraded during protein turnover, thereby covering nutritional as well as other biological roles including protein maturation, hormone level regulation and cell-cycle control (McDonald and Barret, 1986;Christensen et al, 1999). Many of the mammalian enzymes play important functions in cellular processes involved in health and disease and, as a consequence, constitute targets for the pharmaceutical industry (Scornik and Botbol, 2001;Holz et al, 2003;Rigolet et al, 2005;Inguimbert et al, 2005). Some aminopeptidases are also of great interest for their biotechnological and agro-industrial applications (Seppo et al, 2003;FitzGerald and O'Cuinn, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Aminopeptidases

Sanz

2007

Industrial Enzymes

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Section: The Pharmaceutical Industrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aminopeptidases

Sanz

2007

Industrial Enzymes

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“…These results suggest that the brain AT 1 R might be designed to preferentially bind AngIII, or an AngIII-like compound, in mediating blood pressure maintenance. Recent attempts to enhance the bioavailability and potency of EC33 have focused on the synthesis of non-peptidic inhibitors that interact at the S1 and S 0 1 subsites of aminopeptidase A [31].…”

Section: Formation Of Angiotensin Ligands and Their Receptorsmentioning

confidence: 99%

New insights into the importance of aminopeptidase A in hypertension

et al. 2007

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The renin-angiotensin system (RAS) plays an important role in the maintenance of normal blood pressure and the etiology of hypertension; however, minimal attention has been paid to the degradation of the effector peptide, angiotensin II (AngII). Since aminopeptidase A (APA)-deficient mice develop hypertension APA appears to be an essential enzyme in the control of blood pressure via degradation of AngII. The robust hypertension seen in the spontaneously hypertensive rat (SHR) is due to activation of the RAS, and an accompanying decrease in kidney APA. Changes in APA have also been measured during the activation of the RAS in the Goldblatt hypertension model and Dahl salt-sensitive (DSS) rat. The DSS rat shows an elevation in renal APA activity at the onset of hypertension suggesting a protective role against elevations in circulating AngII, followed by decreased APA activity with advancing hypertension. Changes seen in human maternal serum APA activity during preeclampsia are similar to changes measured in renal APA in the DSS rat model. APA activity is higher than during normal pregnancy at the onset of preeclampsia, and with advancing preeclampsia (severe preeclampsia) declines below that seen during normal pregnancy. Serum APA activity is also increased during hormone replacement therapy (HRT), perhaps in reaction to elevated levels of AngII. Thus, it appears important to consider the relationship among activation of the RAS, circulating levels of AngII, and the availability of APA in hypertensive disorders.

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“…16,17 appear after the marker number 6 and are not labeled. No consistent behavior patterns were observed between animals.…”

Section: Perspectivesmentioning

confidence: 99%

“…15 Pursuant to the formulation of The Angiotensin Hypothesis, efforts have been directed to developing inhibitors of APA in the brain as potential antihypertensive agents. 16,17 However, for such agents to be efficacious, there needs to be absolutely certain that brain Ang II is unable to cause pressor effects.…”

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Central Pressor Actions of Aminopeptidase-Resistant Angiotensin II Analogs

Kokje

Wilson²,

Brown³

et al. 2007

Hypertension

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Abstract-Intracerebroventricular administration of angiotensins causes pronounced pressor and dipsogenic responses. The suggestion that angiotensin III rather than angiotensin II is the active peptide in the brain spawned what we call The Angiotensin III Hypothesis. To test this hypothesis, 5 angiotensin II analogs containing zero or one position substitutions conferring resistance to aminopeptidases were administered intracerebroventricularly to determine their pressor and dipsogenic efficacies. Two aminopeptidase-resistant analogs caused significantly greater pressor responses than angiotensin II, whereas 3 analogs caused pressor responses similar to angiotensin II. Latency to cause a pressor response for 4 of the 5 aminopeptidase-resistant angiotensin II analogs was the same as for angiotensin II. There was no detectable formation of 125 I-angiotensin III from 1 of the intracerebroventricularly administered analogs, 125 I-N-Methyl-L-Asp 1 -angiotensin II, indicating its aminopeptidase resistance. Latency to drink also did not differ between the angiotensins. After the initial dipsogenic response, water was removed until 25 minutes after angiotensin administration to avoid interfering with the pressor response. The dipsogenic stimulus was sustained 25 minutes after intracerebroventricular injection of angiotensin II and its aminopeptidase-resistant analogs. Comparison of angiotensin III and angiotensin II showed equivalent pressor responses with similar latencies and durations. The latency to drink was similar for angiotensin III and angiotensin II. However, there was no dipsogenic response to angiotensin III 25 minutes after intracerebroventricular injection. These data do not support The Angiotensin III Hypothesis and suggest that conversion of exogenously applied angiotensin II to angiotensin III is not necessary to cause brain-mediated pressor or dipsogenic responses. Key Words: brain angiotensin receptors Ⅲ intracerebroventricular Ⅲ dipsogenesis Ⅲ metabolism T he brain rennin-angiotensin system (RAS) is distinct from the peripheral RAS and regulated independently. [1][2][3] Hyperactivity of the brain RAS is known to cause hypertension. 4 Angiotensin II (Ang II) receptors in circumventricular organs (which respond to both blood-borne and centrally produced Ang II), as well as in the hypothalamus and brain stem, cause cardiovascular, endocrine, and behavioral effects. 5 Centrally administered angiotensins stimulate both angiotension II type 1 (AT 1 ) and type 2 (AT 2 ) receptor subtypes in the brain, but the cardiovascular effects arise from AT 1 receptor-mediated vasopressin, oxytocin and aldosterone release, activation of sympathetic neuronal activity, and enhanced thirst and salt appetite. 6,7 Fitzsimons demonstrated that angiotensin III (Ang III) which is des Asp 1 Ang II also acts in the brain, to cause thirst. 8 Subsequent studies demonstrated that intracerebroventricular (ICV) Ang II and Ang III were equipotent at causing dipsogenic and pressor responses. 9 Harding and Felix 10 were able to increas...

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Synthesis and in vitro activities of new non‐peptidic APA Inhibitors

Cited by 23 publications

References 15 publications

Aminopeptidases

Aminopeptidases

New insights into the importance of aminopeptidase A in hypertension

Central Pressor Actions of Aminopeptidase-Resistant Angiotensin II Analogs

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