Mass Balance and Absorption, Distribution, Metabolism, and Excretion Properties of Balcinrenone following Oral Administration in Combination with Intravenous Microtracer in Healthy Subjects.

An absorption, distribution, metabolism, and excretion study was performed to determine the basic pharmacokinetic parameters, mass balance, and metabolite profiles of balcinrenone, a mineralocorticoid receptor modulator, in humans. This open-label, single-center, nonrandomized study had a two-period design. In period 1, eight healthy male subjects were dosed with a microtracer intravenous infusion of [C]balcinrenone shortly after receiving an oral dose of unlabeled balcinrenone in a capsule.

Application of Accelerator Mass Spectrometry to Characterize the Mass Balance Recovery and Disposition of AZD4831, a Novel Myeloperoxidase Inhibitor, following Administration of an Oral Radiolabeled Microtracer Dose in Humans.

This study evaluated the mass balance and disposition of AZD4831, a novel myeloperoxidase inhibitor, in six healthy participants using a C-labeled microtracer coupled with analysis by accelerator mass spectrometry (AMS). A single oral dose of 10 mg C-AZD4831 (14.8 kBq) was administered as a solution, and C levels were quantified by AMS in blood, urine, and feces over 336 hours postdose.

Characterization of Clinical Absorption, Distribution, Metabolism, and Excretion and Pharmacokinetics of Velsecorat Using an Intravenous Microtracer Combined with an Inhaled Dose in Healthy Subjects.

This open-label, single-period study describes the human absorption, distribution, metabolism, excretion, and pharmacokinetics of velsecorat (AZD7594). Healthy subjects received inhaled velsecorat (non-radiolabeled; 720 g) followed by intravenous infusion of carbon 14 (C)-velsecorat (30 g). Plasma, urine, and feces were collected up to 168 hours post-dose.

In Situ Cyclization of Native Proteins: Structure-Based Design of a Bicyclic Enzyme.

Increased tolerance of enzymes towards thermal and chemical stress is required for many applications and can be achieved by macrocyclization of the enzyme resulting in the stabilizing of its tertiary structure. Thus far, macrocyclization approaches utilize a very limited structural diversity, which complicates the design process. Herein, we report an approach that enables cyclization through the installation of modular crosslinks into native proteins composed entirely of proteinogenic amino acids.

Synthesis of complex head-to-side-chain cyclodepsipeptides.

Cyclodepsipeptides are cyclic peptides in which at least one amide link on the backbone is replaced with an ester link. These natural products present a high structural diversity that corresponds to a broad range of biological activities. Therefore, they are very promising pharmaceutical candidates.

Structure-Based Design of Inhibitors of Protein-Protein Interactions: Mimicking Peptide Binding Epitopes.

Protein-protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation.

Stellatolides, a new cyclodepsipeptide family from the sponge Ecionemia acervus: isolation, solid-phase total synthesis, and full structural assignment of stellatolide A.

The marine environment is a rich source of metabolites with potential therapeutic properties and applications for humans. Here we describe the first isolation, solid-phase total synthesis, and full structural assignment of a new class of cyclodepsipeptides from the Madagascan sponge Ecionemia acervus that shows in vitro cytotoxic activities at submicromolar concentrations. Seven structures belonging to a new family of compounds, given the general name stellatolides, were characterized.

Rescuing biological activity from synthetic phakellistatin 19.

Phakellistatins is one of the families of Pro-rich cyclic peptides whose synthetic counterparts have revealed cytotoxicities that differ greatly from those displayed by their corresponding natural ones. This is also the case of the last member isolated from this family, phakellistatin19, an octacyclopeptide containing three Pro moieties and a high percentage of apolar residues. Exhaustive NMR studies on the synthetic and natural phakellistatin 19 have been performed in order to find a plausible explanation for this intriguing behavior.

The first total synthesis of the cyclodepsipeptide pipecolidepsin A.

Pipecolidepsin A is a head-to-side-chain cyclodepsipeptide isolated from the marine sponge Homophymia lamellosa. This compound shows relevant cytotoxic activity in three human tumour cell lines and has unique structural features, with an abundance of non-proteinogenic residues, including several intriguing amino acids. Although the moieties present in the structure show high synthetic difficulty, the cornerstone is constituted by the unprecedented and highly hindered γ-branched β-hydroxy-α-amino acid D-allo-(2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L-(2S,3S,4R)-3,4-dimethylglutamine, (2R,3R,4S)-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, D-allo-Thr and L-pipecolic acid.

"Head-to-side-chain" cyclodepsipeptides of marine origin.

Since the late 1980s, a large number of depsipeptides that contain a new topography, referred to as "head-to-side-chain" cyclodepsipeptides, have been isolated and characterized. These peptides present a unique structural arrangement that comprises a macrocyclic region closed through an ester bond between the C-terminus and a β-hydroxyl group, and terminated with a polyketide moiety or a more simple branched aliphatic acid. This structural pattern, the presence of unique and complex residues, and relevant bioactivity are the main features shared by all the members of this new class of depsipeptides, which are reviewed herein.