Design and synthesis of potent macrocyclic renin inhibitors

Sund, Christian; Belda, Oscar; Wiktelius, Daniel; Sahlberg, Christer; Vrang, Lotta; Sedig, Susanne; Hamelink, Elizabeth; Henderson, Ian; Agback, Tatiana; Jansson, Krister N.; Borkakoti, Neera; Derbyshire, D.J.; Eneroth, Anders; Samuelsson, Bertil

doi:10.1016/j.bmcl.2010.10.140

Cited by 17 publications

(12 citation statements)

References 27 publications

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“…Introduction of 4-methoxyphenylalanine at the P 3 position should secure the peptide bond against proteolytic action of chymotrypsin in the gastrointestinal tract. An aromatic ring [15,42] that binds to the hydrophobic pocket S 3sp [16,17,43] is Boc-Phe(4-OMe)-MeLeu-AAHOA -OH C 38 necessary at the P 3 position. The amino group in Phe was substituted by t-butoxycarbonyl (Boc) group that corresponds to a branched alkyl at the P 4 position.…”

Section: Resultsmentioning

confidence: 99%

“…The applied methods are specified later in the syntheses section. Physicochemical properties of the inhibitors 7, 11, 18, 25, as well as newly synthesized intermediates 1, 3,4,6,9,12,13,14,15,16,17,19,20,21,22,23,24, are presented in Tables 2 and 3.…”

Section: Chemistrymentioning

confidence: 99%

“…Hydrophobic interactions with the S 4 and S 2 '-S 3 ' pockets [15] are also important for their inhibitory activity. Recent discovery of sub-pockets within the S 3 and S 1 sites [16,17] that could react with hydrophilic and polar moieties opens new possibility of designing inhibitors that are significantly modified at the P 1 position. By facilitating formation of additional hydrogen bonds, the modifications could lead to enhanced enzyme-inhibitor interactions as shown in Figure 6.…”

Section: Introductionmentioning

confidence: 99%

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Novel renin inhibitors containing derivatives of N‐alkylleucyl‐β‐hydroxy‐γ‐amino acids

Winiecka

Jaworski

Mazurek

et al. 2016

Journal of Peptide Science

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In search for new drugs lowering arterial blood pressure, which could be applied in anti-hypertensive therapy, research concerning agents blocking of renin-angiotensin-aldosteron system has been conducted. Despite many years of research conducted at many research centers around the world, aliskiren is the only one renin inhibitor, which is used up to now. Four novel potential renin inhibitors, having structure based on the peptide fragment 8-13 of human angiotensinogen, a natural substrate for renin, were designed and synthesized. All these inhibitors contain unnatural moieties that are derivatives of N-methylleucyl-β-hydroxy-γ-amino acids at the P2-P1' position: 4-[N-(N-methylleucyl)-amino]-3-hydroxy-7-(3-nitroguanidino)-heptanoic acid (AHGHA), 4-[N-(N-methylleucyl)-amino]-3-hydroxy-5-phenyl-pentanoic acid (AHPPA) or 4-[N-(N-methylleucyl)-amino]-8-benzyloxycarbonylamino-3-hydroxyoctanoic acid (AAHOA). The previously listed synthetic β-hydroxy-γ-amino acids constitute pseudodipeptidic units that correspond to the P1-P1' position of the inhibitor molecule. An unnatural amino acid, 4-methoxyphenylalanin (Phe(4-OMe)), was introduced at the P3 position of the obtained compounds. Three of these compounds contain isoamylamide of 6-aminohexanoic acid (ε-Ahx-Iaa) at the P2'-P3' position. The proposed modifications of the selected human angiotensinogen fragment are intended to increase bioactivity, bioavailability, and stability of the inhibitor molecule in body fluids and tissues. The inhibitor Boc-Phe(4-OMe)-MeLeu-AHGHA-OEt was obtained in the form of an ethyl ester. The hydrophobicity coefficient, expressed as log P varied between 3.95 and 8.17. In vitro renin inhibitory activity of all obtained compounds was contained within the range 10(-6)-10(-9) M. The compound Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa proved to be the most active (IC50 = 1.05 × 10(-9) M). The compounds Boc-Phe(4-OMe)-MeLeu-AHGHA-Ahx-Iaa and Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa are resistant to chymotrypsin.

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Section: Resultsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel renin inhibitors containing derivatives of N‐alkylleucyl‐β‐hydroxy‐γ‐amino acids

Winiecka

Jaworski

Mazurek

et al. 2016

Journal of Peptide Science

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“…Nonetheless, this chemical approach has been used to advantage to prepare both macrocyclic peptidomimetic and non-peptidic compounds, including renin inhibitors, [23][24][25][26][27] thrombin inhibitors (7, Figure 11.1, ring closure site and reagent used for cyclization indicated), 28,29 human immunodeficiency (HIV) protease inhibitors, 30,31 b-secretase (BACE-1) inhibitors, 32 TNF-a converting enzyme (TACE) inhibitors, 33 selective MMP-8 inhibitors, 34 protease inhibitors, 35 calpain inhibitors, 36 cholecystokinin (CCK)-B antagonists, 37 subtype selective somatostatin analogues, 38 growth factor receptor-bound protein 2 (Grb) Src homology 2 (SH2) domain inhibitors, 39 histone deacetylase (HDAC) inhibitors, 40 heat shock protein 90 (Hsp90) inhibitors, 41 PDZ domain ligands, 42 multicyclic mimics of protein loop structures, 43,44 and a wide variety of structures that target the G-quadruplex (8). [45][46][47] For this latter example, it was actually simultaneous double amide bond formation that created the ring.…”

Section: Macrolactamization and Macrolactonizationmentioning

confidence: 99%

“…Also on solid phase, a small collection of macroheterocycles (25) was prepared utilizing an S N 2 process involving a halide and a malonate anion. 67 Other bioactive macrocyclic structures have been assembled using an S N 2 approach including hydroxamic acid MMP and TACE inhibitors, 9,68 cyclindependent kinase (CDK) inhibitors (26, Figure 11.3, ring closure site, base and leaving group indicated), 69 MMP inhibitors (27), 70 thiazole-containing RGD analogues 71,72 and sodium/glucose co-transporter 2 (SGLT2) inhibitors (28) In the construction of the macrocyclic amines 27, it was found that the preferred base varied with ring size, with DBU optimal for 13-membered rings, while DIPEA (N,N-diisopropylethylamine) worked better for 14-membered target molecules.…”

Section: S N 2 Reactionsmentioning

confidence: 99%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

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Fixierung cyclischer Peptide: Mimetika von Proteinstrukturmotiven

et al. 2014

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Viele Proteine entfalten ihre biologische Aktivität über kleine exponierte Oberflächenregionen aus gefalteten Peptiden mit wohldefinierten dreidimensionalen Strukturen, Epitope genannt. Kurze synthetische Peptidsequenzen, die diesen bioaktiven Proteinoberflächen entsprechen, bilden in Wasser keine thermodynamisch stabilen proteinähnlichen Strukturen. Die Bildung proteinähnlicher biologisch aktiver Konformationen (Stränge, Helices, Kehren) kann jedoch durch Cyclisierung in Verbindung mit anderen molekularen Verstrebungen induziert werden. Letztere helfen bei der Feinabstimmung der dreidimensionalen Struktur. Solche fixierten cyclischen Peptide können ähnliche biologische Aktivitäten und Wirkungen wie das als Vorbild dienende Protein haben, sodass sie als biologische Sonden und Leitstrukturen für Therapeutika, Diagnostika und Impfstoffe dienen können. Dieser Aufsatz beleuchtet Beispiele für cyclische Peptide, die dreidimensionale Strukturen von Strang‐, Kehren‐ oder Helixabschnitten von Peptiden und Proteinen nachahmen und beschreibt einige weitere Elemente, die in cyclisch peptidischen Naturstoffen und synthetischen makrocyclischen Peptidomimetika vorkommen, dort die Peptidstruktur verfeinern und ihr biologische Aktivitäten verleihen.

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Design and synthesis of potent macrocyclic renin inhibitors

Cited by 17 publications

References 27 publications

Novel renin inhibitors containing derivatives of N‐alkylleucyl‐β‐hydroxy‐γ‐amino acids

Novel renin inhibitors containing derivatives of N‐alkylleucyl‐β‐hydroxy‐γ‐amino acids

The Synthesis of Macrocycles for Drug Discovery

Fixierung cyclischer Peptide: Mimetika von Proteinstrukturmotiven

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