Structure‐Based Design, Synthesis, and in vitro Evaluation of Nonpeptidic Neprilysin Inhibitors

Sahli, Stefan; Stump, Bernhard; Welti, Tobias; Blum‐Kaelin, Denise; Aebi, Johannes D.; Oefner, Christian; Böhm, Hans‐Joachim; Diederich, François

doi:10.1002/cbic.200400005

Cited by 18 publications

(11 citation statements)

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“…5 ± 25 times higher affinities towards neprilysin compared to the imidazole-based inhibitors [1]. Interestingly, ligand ()-2 (IC 50 0.040 mm ; the higher value given in the preliminary communication [10] is wrong) is seven times more active than ()-1 (IC 50 0.29 mm). The enhanced activity seems to support the modeling-based proposal (Fig.…”

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Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Sahli

Frank

Schweizer

et al. 2005

Helvetica Chimica Acta

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A new class of nonpeptidic inhibitors of the Zn II -dependent metalloprotease neprilysin with IC 50 values in the nanomolar activity range (0.034 ± 0.30 mm) were developed based on structure-based de novo design (Figs. 1 and 2). The inhibitors feature benzimidazole and imidazo [4,5-c]pyridine moieties as central scaffolds to undergo H-bonding to Asn542 and Arg717 and to engage in favorable p-p stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the Zn II ion and an aryl residue to occupy the hydrophobic S1' pocket, but lack a substituent for binding in the S2' pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds ()-1, ()-2, ()-25, and ()-26 were accomplished using Evans auxiliaries (Schemes 2, 4, and 5). The inhibitors ()-2 and ()-26 with an imidazo[4,5-c]pyridine core are ca. 8 times more active than those with a benzimidazole core (()-1 and ()-25) ( Table 1). The predicted binding mode was established by X-ray analysis of the complex of neprilysin with ()-2 at 2.25-resolution (Fig. 4 and Table 2). The ligand coordinates with its sulfanyl residue to the Zn II ion, and the benzyl residue occupies the S1' pocket. The 1H-imidazole moiety of the central scaffold forms the required H-bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes p-p stacking with the side chain of His711 as well as edge-to-face-type interactions with the side chain of Trp693. According to the X-ray analysis, the substantial advantage in biological activity of the imidazopyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N-atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1' pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors.1. Introduction. ± In the preceding paper [1], we described a new class of inhibitors of the metalloprotease neprilysin with a central 1H-imidazole platform, featuring IC 50 values (IC 50 : concentration of inhibitor at which 50% V max is observed) in the low micromolar range. The de novo design of these compounds was based on the X-ray crystal structure of NEP complexed with phosphoramidon (Protein Data Bank (PDB) file name 1DMT) [2]. For the design of the second-generation inhibitors, we reverted to an unpublished X-ray crystal structure [3] of NEP complexed with the inhibitor thiorphan [4]. During the analysis, we carefully compared the active sites of the two

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“…2, b). Here, we report the synthesis of ()-1 and ()-2, and some analogs, their biological activities, and the X-ray crystal structure of NEP bound to inhibitor ()-2 (for a preliminary communication on parts of this work, see [10]). 2.…”

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Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Sahli

Frank

Schweizer

et al. 2005

Helvetica Chimica Acta

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“…7 Besides, as a lead structure benzimidazole has been already used as a part of a central scaffold in some metallo-and serine proteases inhibitors, because of its potential in Hbonding and -stacking interactions with the imidazole ring of His residues essential for the activity of these enzymes. 8 Alternatively, aromatic amidine molecules have been widely studied as competitive inhibitors of the protease enzymes because amidine moieties bind to an aspartic acid residue in the specificity pocket adjacent to the active site of several serine proteases to produce competitive inhibitors. 9 Since proteases have been linked to several disease states, including thrombosis, inflammation, bronchoconstriction, as well as tumor growth and invasion, 20 they are rational targets for inhibition by drugs.…”

Section: Antiviral Properties Of Various Benzimidazole Derivatives Hamentioning

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“…Therefore, numerous biological activities and functions have been described: antihelmintic, 2 antifungal, 3 antiallergic, antimicrobial, 4, 5, 6 antiviral 7 and antineoplastic activity. 8 …”

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Synthesis, Antiviral and Antitumor Activity of 2‐Substituted‐5‐amidino‐benzimidazoles.

et al. 2007

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We have prepared a set of heterocyclic benzimidazole derivatives bearing amidino substituents at C-5 of benzimidazole ring, by introducing various heterocyclic nuclei (pyridine, N-methyl-pyrrole or imidazole) at C-2, and evaluated their antitumor and antiviral activities. The most pronounced antiproliferative activity was shown with compounds 6 and 9, having imidazolinylamidino-substituent. Interestingly, all compounds show remarkable selectivity towards breast cancer cell line MCF-7. The most distinct and selective antiviral activity towards Coxackieviruses and Echoviruses was observed with compounds having pyridine ring at C-2. Especially interesting was fairly strong activity of 4 and 8 toward adenoviruses, which could be considered as leads against adenoviral replication.

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“…This scaffold is elegantly decorated using double directed-ortho-metallation strategies [24]. The firstgeneration ligands, which still contain a Zn II -binding thiol ligand, show IC 50 values in the low micromolar activity range (for a preliminary communication of parts of this work, see [25]; IC 50 : concentration of inhibitor at which 50% V max is observed). Their proposed binding mode is fully validated by the X-ray crystal-structure data reported in the following paper in this issue [26].…”

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A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a Central Imidazole Scaffold

Sahli

Stump

Welti

et al. 2005

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Neprilysin (NEP; neutral endopeptidase EC 3.4.24.11) is a Zn II -dependent, membrane-bound endopeptidase. NEP is widely distributed in the organs, particularly in the kidneys and lungs, and it is involved in the metabolism of a number of smaller regulatory peptides. Inhibition of NEP has been proposed as a potential target for analgesic and antihypertensive therapies. In this study, new nonpeptidic inhibitors of neprilysin ((AE)-1, (AE)-43, (AE)-45, and (AE)-46; Table) were designed, based on the X-ray crystal structure of NEP complexed to phosphoramidon (Fig. 1). They feature an imidazole ring as the central scaffold, acting as a peptide bond isoster to undergo H-bonding with the side chains of Asn542 and Arg717 (Fig. 2). The scaffold is decorated with a thiol group to ligate to the Zn II ion and two aromatic residues to bind into the hydrophobic S1' and S2' pockets. The synthesis of the new inhibitors was approached by two routes (Schemes 1 ± 4 and 5 ± 8), with the second one involving a double directed ortho-metallation of the imidazole platform and a Stille cross-coupling, providing the desired target molecules as hydrochloride salts. In a fluorescence assay, inhibitors (AE)-1, (AE)-43, (AE)-45, and (AE)-46 all exhibit IC 50 values in the single-digit micromolar activity range (2 ± 4 mm, Table), which validates the binding mode postulated by modeling. Useful guidelines for a next lead optimization cycle were obtained in several control runs.

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Structure‐Based Design, Synthesis, and in vitro Evaluation of Nonpeptidic Neprilysin Inhibitors

Cited by 18 publications

References 24 publications

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Synthesis, Antiviral and Antitumor Activity of 2‐Substituted‐5‐amidino‐benzimidazoles.

A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a Central Imidazole Scaffold

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