Long-acting peptidomimetics based DPP-IV inhibitors

Pyrrolidine based peptidomimetics are reported as potent and selective DPP-IV inhibitors for the treatment of T2DM. Compounds 16c and 16d showed excellent in vitro potency and selectivity towards DPP-IV and the lead compound 16c showed sustained antihyperglycemic effects, along with improved pharmacokinetic profile.     

Constrained peptidomimetics as antiplasmodial falcipain-2 inhibitors

Herein we report the synthesis of a series of novel constrained peptidomimetics 2–10 endowed with a dipeptide backbone (d-Ser-Gly) and a vinyl ester warhead, structurally related to a previously identified lead compound 1, an irreversible inhibitor of falcipain-2, the main haemoglobinase of lethal malaria parasite Plasmodium falciparum. The new compounds were evaluated for their inhibition against falcipain-2, as well as against cultured P. falciparum. The inhibitory activity of the synthesized compounds was also evaluated against another protozoal cysteine protease, namely rhodesain of Trypanosoma brucei rhodesiense.     

Synthesis of four diastereomeric enkephalins incorporating cyclopropyl phenylalanine

Four diastereomeric D-Ala2, Leu5-enkephalins have been synthesized and their CD spectra and rat brain binding affinities determined. Only the peptides containing Z-cyclopropyl phenylalanine residues showed strong binding affinity. No correlation between CD spectra and bioactivity could be made.     

Novel peptidomimetics: inhibitors of substance P endopeptidase

The synthesis of the novel bis-phenylalanine mimetic 1 and its incorporation into substance P are described. The key step in the synthesis of 1 is a Julia olefination reaction resulting in a trans-olefin. The synthesized compounds were able to inhibit a human substance P endopeptidase but lacked appreciable affinity for the rat NK₁-receptor.     

Aspartic protease inhibitors. An integrated approach for the design andsynthesis of diaminodiol-based peptidomimetics.

Aspartic proteases play key roles in a variety of pathologies, including acquired immunodeficiency syndrome. Peptidomimetic inhibitors can act as drugs to combat these pathologies. We have developed an integrated methodology for preparing human immunodeficiency virus (HIV)-1 aspartic protease diaminodiol inhibitors, based on a computational method that predicts the potential inhibitory activity of the designed structures in terms of calculated enzyme-inhibitor complexation energies. This is combined with a versatile synthetic strategy that couples a high degree of stereochemical control in the central diaminodiol module with complete flexibility in the choice of side chains in the core and in flanking residues. A series of 23 tetrameric, pentameric and hexameric inhibitors, with a wide range of calculated relative complexation energies (-47.2 to +117 kJ.mol-1) and predicted hydrophobicities (logPo/w = 1.8-8.4) was thus assembled from readily available amino acids and carboxylic acids. The IC50 values for these compounds ranged from 3.2 nM to 90 microM, allowing study of correlations between structure and activity, and individuation of factors other than calculated complexation energies that determine the inhibition potency. Multivariable regression analysis revealed the importance of side-chain bulkiness and rigidity at the P2, P2' positions, suggesting possible improvements for the prediction process used to select candidate structures.     

Novel 3-galloylamido-N'-substituted-2,6-piperidinedione-N-acetamide peptidomimetics as metalloproteinase inhibitors

Both of aminopeptidase N (APN) and matrix metalloproteinase (MMP) are essential metallopeptidases in the development of tumor invasion and angiogenesis. Novel potent peptidomimetic inhibitors, containing 3-galloylamido-N'-substituted-2,6-piperidinedione-N-acetamide, have been designed and synthesized according to the conformational constraint strategy. The preliminary biological test showed that most of the compounds displayed high inhibitory activity against MMP-2 and low activity against APN except compounds 6 (IC(50)=3.1microM) and 4l (IC(50)=5.2microM) which exhibit similar potency to Bestatin (IC(50)=2.4microM).     

Isosorbide-based peptidomimetics as inhibitors of hepatitis C virus serine protease

Hepatitis C infection is a cause of chronic liver diseases such as cirrhosis and carcinoma. The current therapy for hepatitis C has limited efficacy and low tolerance. The HCV encodes a serine protease which is critical for viral replication, and few protease inhibitors are currently on the market. In this paper, we describe the synthesis and screening of novel isosorbide-based peptidomimetic inhibitors, in which the compounds 1d, 1e, and 1i showed significant inhibition of the protease activity in vitro at 100 µM. The compound 1e also showed dose-response (IC₅₀ = 36 ± 3 µM) and inhibited the protease mutants D168A and V170A at 100 µM, indicating it as a promising inhibitor of the HCV NS3/4A protease. Our molecular modeling studies suggest that the activity of 1e is associated with a change in the interactions of S2 and S4 subsites, since that the increased flexibility favors a decrease in activity against D168A, whereas the appearance of a hydrophobic cavity in the S4 subsite increase the inhibition against V170A strain.     

Synthesis and biological evaluation of novel peptidomimetics as rhodesain inhibitors

Novel rhodesain inhibitors were developed by combining an enantiomerically pure 3-bromoisoxazoline warhead with a 1,4-benzodiazepine scaffold as specific recognition moiety. All compounds were proven to inhibit rhodesain with K_i values in the low-micromolar range. Their activity towards rhodesain was found to be coupled to an in vitro antitrypanosomal activity, with IC₅₀ values ranging from the mid-micromolar to a low-micromolar value for the most active rhodesain inhibitor (R,S,S)-3. All compounds showed a good selectivity against the target enzyme since all of them were proven to be poor inhibitors of human cathepsin L.     

Imidazo[1,2-a]pyridine-based peptidomimetics as inhibitors of Akt

We report the design, synthesis, and biological evaluation of imidazopyridine-based peptidomimetics based on the substrate consensus sequence of Akt, an AGC family serine/threonine kinase hyperactivated in over 50% of human tumors. Our ligand-based approach led to the identification of novel substrate mimetic inhibitors of Akt1 featuring an unnatural extended dipeptide surrogate. Compound 11 inhibits Akt isoforms in the sub-micromolar range and exhibits improved proteolytic stability relative to a parent pentapeptide.     

Guanylpiperidine peptidomimetics: potent and selective bis-cation inhibitors of factor Xa

A novel series of rigid P3-guanylpiperidine peptide mimics 3-14 was designed as potential factor Xa and prothrombinase inhibitors. Incorporation into a P2-gly-P1-argininal motif led to highly potent and selective inhibitors. The synthesis and biological activities of these derivatives are reported herein.     

Synthesis and antiviral evaluation of novel peptidomimetics as norovirus protease inhibitors

A series of tripeptidyl transition state inhibitors with new P1 and warhead moieties were synthesized and evaluated in a GI-1 norovirus replicon system and against GII-4 and GI-1 norovirus proteases. Compound 19, containing a 6-membered ring at the P1 position and a reactive aldehyde warhead exhibited sub-micromolar replicon inhibition. Retaining the same peptidyl scaffold, several reactive warheads were tested for protease inhibition and norovirus replicon inhibition. Of the six that were synthesized and tested, compounds 42, 43, and 45 potently inhibited the protease in biochemical assay and GI-1 norovirus replicon in the nanomolar range.     

ACE inhibitors as activators of kinin receptors

Angiotensin converting enzyme (ACE) inhibitors are widely used for treatment of cardiovascular diseases. Studies of interaction of ACE inhibitors with bradykinin receptors have shown that ACE inhibitors potentiate bradykinin effects not only by blocking its inactivation but also by activation of its receptors. The mechanism of activation and also structural features of the kinin B₂R and B₁R receptors by ACE inhibitors have been characterized and amino acid residues involved into kinin receptor coupling to G proteins have been identified. Kinins and their receptors are involved into positive therapeutic effect of ACE inhibitors.     

Past, present and future of ACE inhibitors

This satellite symposium was organised and sponsored by Servier. The aim of the symposium was to evaluate the past 30 years of experience with and the future of angiotensin-converting enzyme (ACE) inhibitors. The session was chaired by R. Ferrari (Ferrara, Italy) and M. Tendera (Katowice, Poland).     

Novel potent 2,5-pyrrolidinedione peptidomimetics as aminopeptidase N inhibitors. Design, synthesis and activity evaluation

A series of novel aminopeptidase N inhibitors with 2,5-pyrrolidinedione scaffold were chemically synthesized. Their preliminary biological activities in enzyme kinetics and cell assay in vitro and anti-metastasis profile in vivo were also evaluated. The results indicated that all the compounds displayed potent inhibitory activity against aminopeptidase N. Compound 8f inhibited aminopeptidase N activity with IC(50) value of 1.0μM and displayed better activity profile in vivo than that of bestatin.     

Potent ACE inhibitors from 5-hydroxy indanone derivatives

A novel triazole derivatives(±)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b]furan-6(2H)-one (12a–j) were designed and synthesized by the reaction between racemic azide and terminal acetylenes under click chemistry reaction conditions followed by biological evaluation as angiotensin converting enzyme (ACE) inhibitors. β-Amino alcohol derivatives of 1-indanone (15a–l) were synthesized from 5-hydroxy indanone, it was reacted with epichlorohydrin and followed by oxirane ring opening with various piperazine derivatives. Among the newly synthesized compounds 12b (IC₅₀: 1.388024 µM), 12g (IC₅₀: 1.220696 µM), 12j (IC₅₀: 1.312428 µM) and 15k (IC₅₀: 1.349671 µM) and 15l (IC₅₀: 1.330764 µM) emerged as most active non-carboxylic acid ACE inhibitors with minimal toxicity comparable to clinical drug Lisinopril.     

Targeting ACE and ECE with dual acting inhibitors

A series of urea analogues related to SA6817 and a GSK phosphonic acid with reported ACE inhibitory activity were prepared and tested for dual ACE and ECE activities. Although excellent ACE and NEP inhibition was achieved, only modest ECE inhibition was observed with one analogue.     

Discovery of novel conformationally restricted diazocan peptidomimetics as inhibitors of interleukin-1beta synthesis

A novel diazocan containing dipeptide mimetic was synthesized via reductive N-N bond cleavage of a pyrazolidino-pyrazolidine using Raney-Ni and evaluated as an ICE inhibitor. This versatile 8-membered ring containing scaffold possesses an N-5 ring nitrogen that was used to explore structure-activity relationships in a cell-based assay measuring inhibition of interleukin-1beta.