Advances in the Development of Non-steroidal Mineralocorticoid-receptor Antagonists

The mineralocorticoid receptor (MR) belongs to the nuclear receptor superfamily and regulates body fluid and electrolyte balance. In the last years, much effort has been put into the development of non-steroidal MR antagonists that overcome the side effects of the marketed steroid drugs, and can be used for the treatment of hypertension and heart failure, among others. Initially, MR was identified in epithelial cells, however it also plays important roles in non-epithelial tissues. In this sense, it is of interest to discover ligands that might induce different MR conformational changes, leading to specific coregulator interactions, which could confer tissue-specific effects. Different series of non-steroidal ligands with diverse central scaffolds has been described, which shows antihypertensive and cardiorenal protective effects. This review covers a description of different non-steroidal MR antagonist families, with special focus on compounds under clinical development. The analysis of the three-dimensional (3D) structures of non-steroidal MR antagonists in complex with the MR ligand-binding domain (LBD), recently reported, highlights the interactions crucial for binding. The structure-activity relationships of known ligands, together with the insights provided by the 3D structures of ligand - LBD MR complexes, could help in the development of non-steroidal MR antagonists with improved properties

General approach for the stereocontrolled construction of the β-lactam ring in amino acid-derived 4-alkyl-4-carboxy-2-azetidinones

The first general approach toward the asymmetric synthesis of 4-alkyl-4-carboxy-2-azetidinones derived from amino acids is described. The stereoselective construction of the β-lactam ring was achieved through base-mediated intramolecular cyclization of the corresponding Nα-chloroacetyl derivatives bearing (+)- or (−)-10-(N,N-dicyclohexylsulfamoyl)isoborneol as chiral auxiliary (ee up to 82%).We thank the Comisión Interministerial de Ciencia y Tecnología (SAF 2000-0147) for financial support. G.G.-N. is a predoctoral fellow from the Ministerio de Ciencia y Tecnología, Spain

Easy access to orthogonally protected α-alkyl aspartic acid and α-alkyl asparagine derivatives by controlled opening of β-lactams

The controlled opening of the N1C2 bond in 1-carbamate-substituted 2-azetidinones derived from amino acids by O- and N-nucleophiles provided a straightforward access to orthogonally protected α-alkyl aspartic acid and asparagine derivatives. The use of DBU or sodium azide as additive is essential for expedient cleavage by amino acids to the corresponding β-aspartic acid dipeptides.This work was supported by CICYT (SAF 2000-0147). G.G.-N. thanks a predoctoral fellow from the Spanish Ministry of Science and Technology

Amino acid-derived 4-alkyl-4-carboxy-2-azetidinones. New insights into β-lactam ring formation and n-deprotection

The preparation and N-deprotection of a series of phenylalanine-derived 2-azetidinones incorporating 2,4-dimethoxybenzyl (Dmb), 2,3,4-, 2,4,6- and 3,4,5-trimethoxybenzyl (Tmb) groups at 1 position are described. The base-promoted cyclization of the corresponding methoxy-substituted Nα-benzyl-Nα-chloroacetyl derivatives to the 1,4,4-trisubstituted azetidinones proceeded with moderate to good yields, except for the 2,4,6-Tmb analogue. In spite of the number and position of the OMe groups, N-unsubstituted β-lactams were obtained by oxidative debenzylation using potassium peroxodisulfate. Alternatively, debenzylation of Pmb, Dmb and Tmb 2-azetidinones with TFA/anisole resulted in concomitant β-lactam opening to α-benzylaspartic acid derivatives

Entry to new conformationally constrained amino acids. First synthesis of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinone derivatives via an intramolecular Nα-Cα-cyclization strategy

A systematic study on the base-assisted intramolecular alkylation of N-benzyl-N-chloroacetyl amino acid derivatives is described. This study resulted in the first concise and versatile route to the preparation of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinones, to be included into the scarce family of β-lactams with quaternary centers at the C4 position. Particularly noteworthy is that the intramolecular Nα-Cα-cyclization of Phe and Leu derivatives afforded the corresponding β-lactam derivatives with moderate enantioselectivity (up to 56%). It is suggested that, in these particular cases, the cyclization reaction proceeds by way of planar enolate intermediates, which possess dynamic chirality. The described sequence of reactions, that is compatible with commonly used protecting moieties for the α-carboxy group, cannot be applied to dipeptides, since the cyclization to the six-membered 2,5-diketopiperazine ring occurrs preferentially.We thank the Comisión Interministerial de Ciencia y Tecnología (SAF 97 0030 and SAF 2000-0147) for financial support. G.G.N. is a predoctoral fellow from the Ministerio de Educación y Cultura, Spain

Exploring solid-phase approaches for the preparation of new β-lactams from amino acids

Two solid-phase approaches, involving the base-assisted intramolecularalkylation of N-chloroacetyl-Phe derivatives anchored to appropriatesolid supports, were investigated for the preparation of novel β-lactams. When a BAL-type strategy was used, the resin-bound azetidinones were easily formed, as established by MAS-NMR, but final compounds could not be removed from the resin, unless a suitable two linkers system was used. In the second approach, in which the Phe residue is anchored to a Wang-type resin through the carboxylate group, the corresponding 1,4,4-trisubstituted 2-azetidinone was obtained in moderate to good yield and high purity

2-Alkyl-2-carboxy-azetidines as scaffolds for the induction of γ-turns

To investigate the ability of 2-alkyl-2-carboxy-azetidines (Azx) to induce reverse turns when incorporated into peptides, RCO-Azx-l-Ala-NHMe dipeptide derivatives were selected as simplified tetrapeptide models, in which the azetidine residue is incorporated at the i + 1 position. Molecular modelling, 1H NMR and FTIR studies showed the high tendency of the model tetrapeptides to adopt γ-turn conformations, indicating that these azetidine-containing amino acids could serve as general γ-turn promoters.This work has been supported by CICYT (SAF 2003-07207-C02 and SAF 2006-01205) and Comunidad de Madrid (GR/SAL/0846/2004). J.L.B. is a predoctoral fellow from the Spanish Ministry of Education and Science

New conformationally constrained tryptophans by N(α)-C(α)-cyclization to an azetidin-2-one core

An entry to new conformationally restricted tryptophans, obtained through N(α)-C(α)-cyclization to an azetidin-2-one core, is described. The yield and ratio of β-lactamization from N(α)-chloroacetyl tryptophan derivatives were dependent on the base and the solvent used. The chemoselective reduction of the β-lactam ring to the corresponding azetidine is also described