Modulating Mineralocorticoid Receptor with Non-steroidal Antagonists. New Opportunities for the Development of Potent and Selective Ligands without Off-Target Side Effects

Steroidal mineralocorticoid receptor (MR) antagonists are used for treatment of a range of human diseases, but they present challenging issues of complex chemical synthesis, undesirable physical properties, and poor selectivity along with unwanted side effects. Therefore, there is a great interest in the discovery of non-steroidal ligands able to bind to the ligand-binding domain of the MR and recruit different co-regulators to produce tissue-specific therapeutic effects. Several academic groups and pharmaceutical companies have been developing a series of non-steroidal ligands that consist of different chemical scaffolds, yielding MR antagonists currently evaluated in clinical studies for the treatment of congestive heart failure, hypertension, or diabetic nephropathy. The main focus of this Perspective is to review the reported structure-activity relationships of the different series of compounds, as well as the structural studies that contribute to a better understanding of the receptor active site and are also helpful for optimization processes.Supported by grants from Ministerio de Economiá y Competitividad (MINECO, Spain; grants BFU2012-39092- C02-02, BFU2013-47089-R, and SAF2015-66275-C2-R), European Cooperation in Science and Technology (COST) action ADMIRE (BM-1301), the European Union Seventh Framework Program “Capacities” (FP7-REGPOT-2012-CT2012- 31637-IMBRAIN), and CSIC (201280E096). Y.R. is grateful to CUNY for being a recipient of the CUNY Chancellor’s Research Fellowship Award for the 2015 - 20162015−2016 Academic YearPeer Reviewe

From 1-acyl-β-lactam human cytomegalovirus protease inhibitors to 1-benzyloxycarbonylazetidines with improved antiviral activity. A straightforward approach to convert covalent to noncovalent inhibitors

Starting from the structure of known β-lactam covalent human cytomegalovirus (HCMV) protease inhibitors and from the knowledge of the residues implicated in the active site of this enzyme, we designed a series of phenylalanine-derived 2-azetidinones bearing a 4-carboxylate moiety that could be apt for additional interactions with the guanidine group of the Arg165/Arg166 residues of the viral protease. Some compounds within this series showed anti-HCMV activity at 10−50 μM, but rather high toxicity. The presence of aromatic 1-acyl groups and a certain hydrophobic character in the region of the 4-carboxylate were stringent requirements for anti-HCMV activity. To go a step ahead into the search for effective HCMV medicines, we then envisaged a series of noncovalent inhibitors by simple deletion of the carbonyl group in the β-lactam derivatives to provide the corresponding azetidines. This led to low micromolar inhibitors of HCMV replication, with 17 and 27 being particularly promising lead compounds for further investigation, although their toxicity still needs to be lowered.This work was supported by CICYT (SAF2003-07207-C02) and Geconcerteerde Onderzoeksacties-Vlaanderen (GOA-00/12). G.G.-N. acknowledges a predoctoral fellowship from the Spanish Ministry of Science and Technology (1998-2002)

Synthesis and anti-HCMV activity of 1-acyl-β-lactams and 1-acylazetidines derived from phenylalanine

Different Phe-derived 1-acyl-β-lactams, analogous to a series of 2-azetidinones acting as HCMV serine protease inhibitors, were synthesized. Some of these compounds were modest inhibitors of the HCMV replication. Interestingly, removal of the carbonyl group of the β-lactam ring, most likely acting as the serine trap, resulted in an azetidine derivative with anti-HCMV activity comparable to that of the reference compound ganciclovir.This work was supported by CICYT (SAF 2000-0147 and 2003-07207-C02) and Geconcerteerde Onderzoeksacties–Vlaanderen (GOA-00/12). G.G.-N. holds a predoctoral fellowship from the Spanish Ministry of Science and Technology

Further evidence for 2-alkyl-2-carboxyazetidines as γ-turn inducers

9 pags, 5 figs, 1 tab. -- Supporting Information is available at the Publisher's web(Chemical Equation Presented) Reverse turns, a common motif in proteins and peptides, have attracted attention due to their relevance in a wide variety of biological processes. In an attempt to artificially imitate and stabilize these turns in short peptides, we have developed versatile synthetic methodologies for the preparation of 2-alkyl-2-carboxyazetidines and incorporated them into the i + 1 position of model tetrapeptides, where they have shown a tendency to induce γ-turns. However, to ascertain the general utility of these restricted amino acids as γ-type reverse turn inducers, it was then required to study the conformational preferences when located at other positions. To this end, model tetrapeptides R-CO-Ala-Xaa-NHMe, containing differently substituted azetidine moieties (Xaa = Aze, 2-MeAze, 2-BnAze) at the i + 2 position, were synthesized and subjected to a thorough conformational analysis. The theoretical and experimental results obtained, including the X-ray diffraction structure of a dipeptide derivative containing this skeleton, provide evidence that the 2-alkyl-2-carboxyazetidine scaffold is able to efficiently induce γ-turns when incorporated into these short peptides, irrespective of their localization in the peptide chain. © 2009 American Chemical Society.This work has been supported by CICYT (SAF 2006-01205). J.L.B. was a predoctoral FPI fellow. The “Centro Técnico de Informática (CTI-CSIC)” granted computer time

Cyclic amino acid linkers stabilizing key loops of brain derived neurotrophic factor

Based on β-turn-like BDNF loops 2 and 4, involved in receptor interaction, cyclic peptide replicas were designed, synthesized and tested. In addition to the native turn residues, the cyclic peptides include a linker unit between the N- and C-termini, selected by molecular modeling among various non-proteinogenic cyclic amino acids. NMR conformational studies showed that most of the cyclic peptides were able to adopt turn-like structures. Several of the analogues displayed significant inhibition of the BDNF-induced TrkB receptor phosphorylation, and hence could be useful templates for developing improved antagonists for this receptor. © 2011 Elsevier Ltd. All rights reserved.Peer Reviewe