An efficient stereoselective synthesis of [3S(1S,9S)]-3-[[[9-(benzoylamino)octahydro-6,10-dioxo-6H-pyridazino-(1,2-a)(1,2)-diazepin-1-yl]-carbonyl]amino]-4-oxobutanoic acid, an interleukin converting enzyme (ICE) inhibitor

Chen, M.H.; Goel, O. P.; Hyun, J.‐W.; Magano, Javier; Rubin, John R.

doi:10.1016/s0960-894x(99)00236-x

Cited by 19 publications

(8 citation statements)

References 11 publications

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“…For Ss APN, additional extended phosphinic analogs, which were at least tripeptides, reportedly exhibited similar levels of inhibition. 55 , 56 Doubled modifications were less favorable for Nm APN than for Ss APN, possibly indicating that the adverse constraints were caused by two strong interactions.…”

Section: Results and Discussionmentioning

confidence: 99%

Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases

et al. 2014

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Seven crystal structures of alanyl aminopeptidase from Neisseria meningitides (the etiological agent of meningitis, NmAPN) complexed with organophosphorus compounds were resolved to determine the optimal inhibitor–enzyme interactions. The enantiomeric phosphonic acid analogs of Leu and hPhe, which correspond to the P1 amino acid residues of well-processed substrates, were used to assess the impact of the absolute configuration and the stereospecific hydrogen bond network formed between the aminophosphonate polar head and the active site residues on the binding affinity. For the hPhe analog, an imperfect stereochemical complementarity could be overcome by incorporating an appropriate P1 side chain. The constitution of P1′-extended structures was rationally designed and the lead, phosphinic dipeptide hPhePψ[CH2]Phe, was modified in a single position. Introducing a heteroatom/heteroatom-based fragment to either the P1 or P1′ residue required new synthetic pathways. The compounds in the refined structure were low nanomolar and subnanomolar inhibitors of N. meningitides, porcine and human APNs, and the reference leucine aminopeptidase (LAP). The unnatural phosphinic dipeptide analogs exhibited a high affinity for monozinc APNs associated with a reasonable selectivity versus dizinc LAP. Another set of crystal structures containing the NmAPN dipeptide ligand were used to verify and to confirm the predicted binding modes; furthermore, novel contacts, which were promising for inhibitor development, were identified, including a π–π stacking interaction between a pyridine ring and Tyr372.

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Section: Results and Discussionmentioning

confidence: 99%

Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases

et al. 2014

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“…The following substrates were used for the determination of enzymatic activity: H-Ala-pNA-HCl for APN; H-Glu-pNA-2HCl (both from Bachem, Weil am Rhein, Germany) for APA; H-Leu-pNA-HCl (Sigma, Taufkirchen, Germany) plus RB3014 [specific inhibitor of APN, kindly provided by B.P. Roques (Département de Pharmacochimie Moléculaire et Structurale INSERM U266 - CNRS UMR 8600 UFR des Sciences Pharmaceutiques et Biologiques, Paris, France) ( 42 ) ] for IRAP; Mca-APK (Dnp; Enzo/Biomol, Hamburg, Germany) for ACE2. All the assays were carried out in 50 mM HEPES buffer containing 200 mM NaCl, 10 μM ZnCl 2 and 1% DMSO pH 6.8.…”

Section: Methodsmentioning

confidence: 99%

High glucose activates the alternative ACE2/Ang-(1-7)/Mas and APN/Ang IV/IRAP RAS axes in pancreatic β-cells

Härdtner

Mörke

Walther

et al. 2013

International Journal of Molecular Medicine

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The activation of the classical angiotensin (Ang)-converting enzyme (ACE)/Ang II/Ang II type 1 receptor (AT1R) axis of the renin-angiotensin system (RAS) has been associated with islet dysfunction and insulin resistance. Hyperglycaemia, hypertension and obesity, major components of metabolic syndrome, are all associated with increased systemic and tissue levels of Ang II. Whereas it is well established that Ang II, by binding to AT1R, impairs glucose-stimulated insulin secretion and insulin signaling, the contribution of alternative RAS axes to β-cell function remains to be fully elucidated. In this study, using the BRIN-BD11 rat insulinoma cell line, we i) examined the basal expression levels of components of classical and alternative RAS axes and ii) investigated the effects of normal (5.5 mM) and elevated (11, 15, 25 mM) glucose concentrations on their expression and/or enzymatic activity by means of reverse transcription quantitative PCR (RT-qPCR), immunoblot analysis and enzymatic activity assays. The results correlated with the insulin production and release. Essential components of all RAS axes were found to be expressed in the BRIN-BD11 cells. Components of the alternative RAS axes, ACE2, neutral endopeptidase 24.11, Mas receptor (Mas), aminopeptidases A (APA) and N (APN) and insulin-regulated aminopeptidase (IRAP) showed an increased expression/activity in response to high glucose. These alterations were paralleled by the glucose-dependent increase in insulin production and release. By contrast, components of the classical RAS axis, ACE, AT1R and Ang II type 2 receptor (AT2R), remained largely unaffected under these conditions. Glucose induced the activation of the alternative ACE2/Ang-( 1 - 7 )/Mas and APN/Ang IV/IRAP RAS axes simultaneously with the stimulation of insulin production/release. Our data suggest the existence of a functional link between the local RAS axis and pancreatic β-cell function; however, further studies are required to confirm this hypothesis.

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“…Incorporating (R)- β 2 hVal 1 and Aia 4 -Gly 5 gave a compound that is highly selective and stable and has a high inhibitory effect (AL-40, Figure 9) [168, 170]. Ang IV itself is only a weak inhibitor of the catalytic activity of IRAP, as has been shown by experiments with the metabolically stable tritiated Ang IV analogue [ 3 H]AL-11, in combination with the selective AP-N inhibitor 7B which is a phosphinic transition-state analogue [171] and in the absence of metal chelators. Adding metal chelators creates the apoform of IRAP [167, 172], and it is important to note that the active form and apoforms of IRAP react differently [173].…”

Section: Inhibitors Of Insulin-regulated Aminopeptidasementioning

confidence: 99%

“…Previous conformational analyses of Ang II suggested that such a macrocyclic system would tend to adopt an inverse γ -turn [181, 182], and the replacement of His-Pro-Phe by a 2-(aminomethyl)phenylacetic acid moiety designed to mimic an inverse γ -turn resulted in compound 9 (Figure 10). This compound has a K i value of 44 nM and a much simpler structure than previous candidates [171]. …”

Section: Inhibitors Of Insulin-regulated Aminopeptidasementioning

confidence: 99%

Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers

Andersson

Hallberg

2012

International Journal of Hypertension

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The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins.

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An efficient stereoselective synthesis of [3S(1S,9S)]-3-[[[9-(benzoylamino)octahydro-6,10-dioxo-6H-pyridazino-(1,2-a)(1,2)-diazepin-1-yl]-carbonyl]amino]-4-oxobutanoic acid, an interleukin converting enzyme (ICE) inhibitor

Cited by 19 publications

References 11 publications

Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases

Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases

High glucose activates the alternative ACE2/Ang-(1-7)/Mas and APN/Ang IV/IRAP RAS axes in pancreatic β-cells

Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers

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