New Renin Inhibitors Containing Pseudodipeptidic Units in P3-P2 and P1-P1' Positions

Paruszewski, Ryszard; Jaworski, Paweł; Bodnar, Magdalena; Dudkiewicz-Wilczyńska, Jadwiga; Roman, Iza

doi:10.1248/cpb.53.1305

Cited by 1 publication

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“…The most active compound was Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa 18, featuring IC 50 = 1.3 × 10 À9 M. For comparison, activity of aliskiren amounts to IC 50 = 0.6 × 10 À9 M [28]. Structure of the compounds we obtained was designed on the basis of the fragment of human angiotensinogen and considerably differs from the aliskiren's structure [15,29,30]. Renin inhibition activity, expressed as IC 50 , of inhibitors obtained by our team ranged from 10 À3 M to 10 À7 M. Structure of the said compounds was developed on the basis of the structure of the renin substrate's fragment.…”

Section: Resultsmentioning

confidence: 99%

“…Our aim was to find out whether a probable intra-molecular relationship between the side chains at P 2 and P 1 , that are located closely to each other, could reduce or enhance hydrophobic interactions of the inhibitor with the enzyme. The compounds synthesized by us previously [29,31,32], which contained flexible and branched isobutyl side chains at P 2 and P 1 , have only moderate inhibitory activity, for example, Boc-Phe(4-OMe)-MeLeu-Sta-Ahx-EA IC 50 = 2.5 × 10 À4 M [33]. In this case, however, moderate activity could result from the presence of hydrophilic ethanolamine (EA) at the P 3 ' position of the C-terminus.…”

Section: Resultsmentioning

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: Resultsmentioning

confidence: 99%