A series of short tryptophan-phenylalanine peptides containing an iodo substituent on the phenyl ring was subjected to Pd-catalyzed CH activation reactions to give the corresponding aryl-indole coupled products. Two types of adducts were generated: cyclomonomer and cyclodimeric peptides; no evidence of oligo- or polymerization products was detected. Contrary to standard peptide macrocyclizations, the factors controlling the fate of the reaction are the number of amino acids between the aromatic residues and the regiochemistry of the parent iodo derivative, independent of both the concentration and the cyclization mode. The method is general and allows access to novel biaryl peptidic topologies, which have been fully characterized.

Matrix metalloproteinases (MMPs) are synthesized by neurons and glia and released into the extracellular space, where they act as modulators of neuroplasticity and neuroinflammatory agents. Development of epilepsy (epileptogenesis) is associated with increased expression of MMPs and therefore they may represent potential therapeutic drug targets. Using qPCR and immunohistochemistry, we studied the expression of MMPs and their endogenous inhibitors TIMPs, in patients with status epilepticus (SE) or temporal lobe epilepsy (TLE), and in a rat TLE model. Furthermore, we tested the MMP2/9 inhibitor IPR-179 in the rapid kindling rat model and in the intrahippocampal kainic-acid mouse model. In both human and experimental epilepsy, MMP and TIMP expression was persistently dysregulated in the hippocampus compared to controls. IPR-179 treatment reduced seizure severity in the rapid kindling model and reduced the number of spontaneous seizures in the kainic-acid model (during and up to 7 weeks after delivery) without side effects while improving cognitive behavior. Moreover, our data suggest that IPR-179 prevented an MMP2/9-dependent switch-off normally restraining network excitability during the activity period. Since increased MMP expression is a prominent hallmark of the human epileptogenic brain and the MMP inhibitor IPR-179 has antiseizure and antiepileptogenic effects in rodent epilepsy models and attenuates seizure-induced cognitive decline, it deserves further investigation in clinical trials. Funding: The research leading to these results has received funding from the European Union's

No abstract

New chemotypes are obtained from tryptophan-containing diketopiperazines through selective C-C or C-N intramolecular oxidative couplings. The choice of the oxidant source dictates the outcome of the reaction.

<b><i>Introduction:</i></b> Evidence on the prevalence of uncontrolled asthma upon the standard of care in Japan is scarce and inconsistent. We report the prevalence of uncontrolled asthma using the Japanese Guidelines for Asthma (JGL) 2018 and Global Initiative for Asthma (GINA) 2019 classifications in patients who are currently receiving standard-of-care treatment in a real-life setting. <b><i>Methods:</i></b> In this prospective, 12-week, noninterventional study, patients with asthma aged 20–75 years and continuously treated with medium- or high-dose inhaled corticosteroid (ICS)/LABA, with or without other controller(s), were assessed for their asthma control status. The demographics, clinical characteristics, treatment patterns, health care resource utilization, patient-reported outcomes (PROs), and adherence to prescribed treatments were assessed for patients classified as either controlled or uncontrolled. <b><i>Results:</i></b> Of 454 patients, 53.7% and 36.3% of the patients reported their asthma as uncontrolled based on the JGL and GINA criteria, respectively. Uncontrolled asthma was even higher (JGL, 75.0%; GINA, 63.5%) within the subpopulation of 52 patients receiving long-acting muscarinic antagonists (LAMAs; i.e., ICS/LABA/LAMA subpopulation). Sensitivity analysis by propensity matching identified significant odds ratios of controlled versus uncontrolled asthma for several demographics and clinical characteristics: male; sensitization to animals, fungi, or birch; comorbidities including food allergy or diabetes; and history of exacerbation were associated with the risk of uncontrolled asthma. No significant changes in PROs were observed. <b><i>Conclusion:</i></b> The frequency of uncontrolled asthma in the study population was high, as per JGL and GINA guidelines, despite good adherence to ICS/LABA treatment and other prescribed treatments over 12 weeks.