Subsite requirements for peptide aldehyde inhibitors of human calpain I

doi:10.1016/S0960-894X(97)00063-2

Bioorganic & Medicinal Chemistry Letters

Volume 7, Issue 5, 4 March 1997, Pages 539-544

https://doi.org/10.1016/S0960-894X(97)00063-2 Get rights and content

Abstract

Dipeptide and tripeptide aldehydes have been evaluated as inhibitors of human calpain I. Dipeptide aldehydes are generally equipotent with tripeptide aldehydes. Calpain I possesses a rather stringent requirement for Leu at P₂, but accepts a variety of capping groups and amino acids at P₁ and P₃. Several new peptide aldehydes that are more potent than previously reported calpain I inhibitors have been identified.

Dipeptide and tripeptide aldehydes have been evaluated as inhibitors of human calpain I. Dipeptide aldehydes are generally equipotent with tripeptide aldehydes. Several new peptide aldehydes that are more potent than previously reported calpain I inhibitors have been identified.

References (10)

S. Mehdi
Trends Biochem. Sci.
(1991)
K.K.W. Wang
Trends Pharmacol. Sci.
(1990)
K.K.W. Wang et al.
Trends Pharmacol. Sci.
(1994)
K. TakahashiT. Murachi et al.
T. Sasaki et al.
J. Biol. Chem.
(1984)
S.-C. Hong et al.
Stroke
(1994)
J. Jurczak et al.
Chem. Rev.
(1989)

There are more references available in the full text version of this article.

Cited by (42)

Synthesis and antiproliferative activity of sulfonamide-based peptidomimetic calpain inhibitors
2020, Bioorganic and Medicinal Chemistry
Citation Excerpt :
Compound 1 with l-valine as the P2 substituent was 15-fold more potent than 2, which has a proline residue at the P2 position. This is consistent with previous structure–activity relationship studies, which demonstrated that the S2 subsite of calpain prefers small hydrophobic groups at the P2 position of inhibitors.16 The ethylene-bridged analogues 4 and 5, with Ki values of 14 nM and 9 nM, respectively, were also potent inhibitors of μ-calpain, suggesting that the diazene group is not required for potent inhibition of calpain.
The calpains are a conserved family of cysteine proteases that includes several isoforms of which µ–calpain and m-calpain are the most widely distributed in mammalian cells. Calpains have been implicated in normal physiological processes as well as cellular abnormalities such as neurodegenerative disorders, cataract, and cancer. Therefore, calpain inhibitors are of interest as potential therapeutic agents. We have synthesized four new sulfonamide-based peptidomimetic compounds 2–5 as inhibitors of μ-calpain that incorporate (E)-1-(phenyl)-2-phenyldiazene and (E)-1-(phenyl)-2-phenylethene functionalities as the N-terminal capping groups of the inhibitors. Compound 5 with K_i value of 9 nM versus μ-calpain was the most potent member of the group. The compounds were predicted to be more lipophilic compared to MDL28170 based on CLogP estimation. They displayed moderate to good antiproliferative activity versus melanoma cell lines (A-375 and B-16F1) and PC-3 prostate cancer cells in vitro. Additionally, one member of the group (compound 3) inhibited DU-145 cell invasion by 80% at 2 μM concentration in the Matrigel cell invasion assay.
A new and general method for the synthesis of tripeptide aldehydes based on the multi-component Ugi reaction
2009, Tetrahedron
Citation Excerpt :
Among them, an anti-inflammatory agent 1,1 an antibiotic 2,2 anti-parasitic agents,3 and human rhinovirus 3C protease inhibitors4 can be found (Fig. 1). Tripeptides with C-terminal aldehyde groups are reported as serine, cysteine, and aspartic inhibitors of proteasomes 3,5 human rhinovirus 3C protease 4,6 cathepsin K,7 inhibitors,8 and activators9 of calpains. A special attention is paid to N-benzyloxycarbonyl-l-Leu-l-Leu-l-leucinal (5), a potent and selective inhibitor of 20S proteasome, which is often used as a reference in biomedical studies (Fig. 1).5
Tripeptide aldehydes, such as Z-Leu-Leu-Leu-H (MG-132), are an important class of compounds due to their biological activity. A new, general method for the synthesis of tripeptide aldehydes based on the multi-component Ugi reaction was developed. A careful choice of isocyanides makes it possible to obtain tripeptide precursors whose functionalization led to target structures. This method can be used for the preparation of tripeptide aldehydes with non-natural amino acid side chains.
Ring closing metathesis of α- and β-amino acid derived dienes
2006, Journal of Organometallic Chemistry
Three new classes of conformationally constrained peptidomimetics, derived from modified α- and β-amino acids, have been prepared by ring closing metathesis (RCM). The first involves C_α–N′ cyclisation of the peptidic diene (23, 24, 26), the second C_β2–N′ cyclisation (27, 28, 29), and the third N–C_β2 cyclisation (30). The key C-centred olefin of the dienes was introduced by stereoselective α-allylation of either an α- or β-amino acid. The normal favourable influence of a tertiary amide linker in the diene towards RCM is negated by significant steric congestion, and the combination of a secondary amide linker and α,α-disubstitution promotes ring contraction on RCM.
Exploration of orally available calpain inhibitors. Part 3: Dipeptidyl α-ketoamide derivatives containing pyridine moiety
2006, Bioorganic and Medicinal Chemistry
Calpain-mediated proteolysis has been implicated as a major process in neuronal cell death including retinal neurological degeneration. The previously reported calpain inhibitor SJA6017 (1) showed oral efficacy in a retinal pharmacological model, but its oral bioavailability was low due to the metabolic lability and low water-solubility. The purpose of present study was to identify good orally bioavailable calpain inhibitors. A series of water-soluble dipeptidyl α-ketoamides containing a pyridine moiety at P3 were designed, synthesized, and evaluated for their oral bioavailability and retinal penetration. Introduction of a pyridineethanol moiety provided the potent α-ketoamide inhibitor 8 with good oral bioavailability. Compound 8 showed about 12-fold higher retinal AUC than 1.
A novel series of urea-based peptidomimetic calpain inhibitors
2006, Bioorganic and Medicinal Chemistry Letters
Novel dual inhibitors of calpain and lipid peroxidation with enhanced cellular activity
2006, Bioorganic and Medicinal Chemistry Letters
A series of dipeptides with dual inhibitory activities on calpain and lipid peroxidation were prepared to target the intracellular calpain. This optimization program focused on the variations of the linker and the N-terminal amino acid of the peptidic core. Two compounds 6d-05 and 6d-08 exhibited potent intracellular calpain inhibition. The polar surface area and the number of rotors appeared to be critical descriptors to account for the behavior of these hybrid molecules in the cellular calpain assay.

View all citing articles on Scopus

View full text

Subsite requirements for peptide aldehyde inhibitors of human calpain I

Abstract

Trends Biochem. Sci.

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

J. Biol. Chem.

Stroke

Chem. Rev.