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

Abstract

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.

Non-Canonical Amino Acids in Analyses of Protease Structure and Function

“…Renin inhibitors, derived from angiotensinogen residues 8–13, were synthesized with two uAAs, e.g., Phe(OMe) in the P3 and P2 position, Sta and two pseudo-dipeptides in P1-P1′ and P2′-P3′ [ 282 ]. In addition, when incorporated into Boc-Tyr(OMe)-His-AHNA-OEt, a renin inhibitor with β-hydroxy-γ-amino acids, such as 4-amino-3-hydroxynonanoic acid (AHNA), turned out to be a potent compound with an IC 50 of 13 nM, and the related compound Boc-Tyr(OMe)-MeLeu-AHPPA-ε-Ahx-Iaa had an IC 50 of about 1 nM [ 283 , 284 ]. Due to drug resistance, new inhibitor strategies are constantly developed against viral proteases involved in diseases like AIDS and hepatitis [ 285 ].…”

The Importance of 6-Aminohexanoic Acid as a Hydrophobic, Flexible Structural Element

“…Ahx has also been inserted into the structures of potential low molecular enzyme inhibitors with a peptide structure designed on the basis of a fragment of human angiotensinogen, e.g., renin inhibitors [47]. The compound, containing Ahx-Iaa at the P2'-P3' Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa (IC 50 = 1.05 × 10 −9 M), could enter into hydrophobic interactions at the S2 -S3 site of the enzyme.…”