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Arrhythmogenic cardiomyopathy (ACM) is a rare inherited cardiomyopathy (CMP) characterized by progressive fibro–adipose replacement of the myocardium. It is mainly caused by variants in desmosomal genes with autosomal dominant transmission and incomplete penetrance. Originally, ACM was considered a CMP with main if not exclusive involvement of the right ventricle (RV) and more rarely both ventricles. To date, recent data have also highlighted the possibility of isolated left ventricular (LV) involvement, which often results in a disease with peculiar and distinct features. The case we propose is that of a 70–year–old man with no cardiology history but a family history of cardiomyopathy (brother has unspecified cardiomyopathy and is an ICD carrier). In 2015 due to occasional finding of ventricular extrasystole, the patient underwent CVG which was negative and cardiac MRI which documented an area of late–Gadolinium Enhancement (LGE) of the mid–basal portion of the inferior and lateral wall, with greater involvement of the subepicardial versant of the LV of possible post–myocarditis involvement. In September 2023, he was admitted to our cardiology department following a syncopal episode not preceded by prodromes. The ECG showed poor R–wave progression, low voltages and diffuse repolarization changes. The echocardiogram showed dilated LV with reduced EF(35%). Both CVG and cardiac MRI was repeated. The first was still negative and cardiac MRI showed a considerable progression of LGE areas at the mesomyocardial and subendocardial levels, with an almost ubiquitous distribution in the LV. Additional areas of LGE were also appreciated at the atrioventricular valves, the interatrial septum, and in the RV, but the latter was not dysfunctional. These findings appeared compatible with LV ACM with initial biventricular extension. It was decided to implant ICD in primary prevention and to request genetic analysis, which is still ongoing. Beyond the unusual appearance in extent and locations of areas of LGE on cardiac MRI, our clinical case highlights the close correlation that is often present between left ACM and acute myocarditis. It is not well known whether the inflammation associated with acute myocarditis is a primary injury that results in fibroadipose replacement or whether it is the degeneration of the cardiomyocytes themselves that results in these inflammatory phases (hot–phases) with myocarditis–like expression.

The aim of this review is to highlight the advances in the field of heme oxygenase-1 (HO-1) inhibitors over the past years, particularly from a medicinal chemistry point of view; progresses made in the field strongly helped to clarify physiological roles of the heme oxygenase (HO) system. HO is a family of ubiquitously expressed enzymes which regulate the regiospecific catabolism of heme leading to the formation of equimolar amounts of carbon monoxide (CO), ferrous iron (Fe++), and biliverdin. HO exists in two distinct, catalytically active isoforms: HO-1 and HO-2. HO-1 is an inducible 32-kDa protein, while HO-2 is a constitutively synthesized 36-kDa protein and generally is unresponsive to any of the inducers of HO-1. A third isoform, HO-3, is still an elusive protein. The HO system, along with its catabolism products, is involved in a variety of crucial physiological functions, including cytoprotection, inflammation, anti-oxidative effects, apoptosis, neuro-modulation, immune-modulation, angiogenesis, and vascular regulation. The use of selective HO inhibitors is a very important tool to clarify the role of the HO system and the mechanisms underlying its physiological effects and pathological involvement; due to the inducible nature of HO-1, selective inhibition of HO-1 isoform is generally preferable. Notably, HO-1 inhibitors may be also beneficial in therapeutic applications and have been mainly studied for treatment of hyperbilirubinemia and certain types of cancer. Historically, the first molecules used as non selective HO-1 inhibitors were metalloporphyrins (Mps). The subsequent development of the imidazole-dioxolane derivatives afforded the first generation of non-porphyrin based, isozyme selective HO-1 inhibitors.

The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is one of the most studied neurotransmitters in the central nervous system. It acts through the activation of at least fourteen 5-HT receptor subtypes. Over the last two decades, high attention was devoted to the 5-HT3 and 5-HT4 receptors due to their colocalization in the gastrointestinal tract and because their ligands are useful in the treatment of intestinal serotonergic system dysfunctions. The focus of this review is to discuss the literature concerning recent advances on 5-HT3R and 5-HT4R ligands and their structure-activity relationships from a medicinal chemistry perspective. During the last few years, new and significant progresses have been made in the field of novel potent and selective ligands, mixed ligands, agonists, partial agonists, and antagonists, and a number of patents have been filed. Furthermore several ligands targeting the 5-HT3R and 5-HT4R have been proposed for novel therapeutic indications such as the treatment of various psychiatric disorders.

In the present study we describe the synthesis of a new series of 1,2,4-triazoles: [3-(arylmethyl)thio-5-aryl-4H- [1,2,4]triazol-4-yl]acetic acids 5a-g, [5-(arylmethyl)thio-3-aryl-1H-[1,2,4]triazol-1-yl]acetic acids 8a-d, and [3-(arylmethyl) thio-5-aryl-1H-[1,2,4]triazol-1-yl] acetic acids 9a-d. These compounds were tested in binding assays to evaluate their ability as ligands for human ETA and ETB receptors stably expressed in CHO cells; some of the tested compounds showed affinity in the micromolar range.

In this paper we report the synthesis and the inhibition on Human Leucocyte Elastase (HLE) of a new series of thieno[2,3-d][1,3]oxazin- or thioxazin-4-ones 3a-o and thieno[3,2-d][1,3]oxazin- or thioxazin-4-ones 6a-d. New derivatives have inhibitory activity in the micromolar range and among them, 2-(3- trifluoromethylphenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one 3h and 5,6-dimethyl-2-(4-nitrophenylamino)- 4H-thieno[2,3-d][1,3]thioxazin-4-one 3o were the most interesting.

Novel compounds characterized by a pyrrolo[3,2-d]pyrimidine-2,4-dione (PPm) system connected through an alkyl chain to a phenylpiperazine (PPz) residue were designed as structural analogues of the α1-adrenoceptor (α1-AR) ligand RN5 (1). In this new series of derivatives an arylpyrrolo moiety has replaced the indole nucleus of RN5. Several structural modifications were performed on the PPm and PPz moieties and the connecting alkyl chain. These compounds were synthesized and tested in radioligand binding experiments where many of them showed interesting binding profiles. Some compounds, including 31, 34, and 36, displayed substantial α1-AR selectivity with respect to serotoninergic 5-HT1A and dopaminergic D1 and D2 receptors. Two different molecular modeling approaches (pharmacophoric mapping and quantitative structure−affinity relationship analysis) have been applied to rationalize, at a quantitative level, the relationships between affinity toward α1-ARs and the structure of the studied compounds. Several QSAR models have been reported and described, accounting for the influence of various molecular portions on such affinity data.

Selective inhibitors of neuronal nitric oxide synthase (nNOS), which are devoid of any effect on the endothelial isoform (eNOS), may be required for the treatment of some neurological disorders. In our search for novel nNOS inhibitors, we recently described some 1-[(Aryloxy)ethyl]-1H-imidazoles as interesting molecules for their selectivity for nNOS against eNOS. This work reports a new series of 1-[(Aryloxy)alkyl]-1H-imidazoles in which a longer methylene chain is present between the imidazole and the phenol part of molecule. Some of these molecules were found to be more potent nNOS inhibitors than the parent ethylenic compounds, although this increase in potency resulted in a partial loss of selectivity. The most interesting compound was investigated to establish its mechanism of action and was found to interact with the tetrahydrobiopterin (BH4) binding site of nNOS, without interference with any other cofactors or substrate binding sites.

Nitric oxide (NO) mediates a series of physiological processes, including regulation of vascular tone, macrofage-mediated neurotoxicity, platelet aggregation, learning and long-term potentiation, and neuronal transmission. Although NO mediates several physiological functions, overproduction of NO can be detrimental and play multiple roles in several pathological diseases. Accordingly, more potent inhibitors, more selective for neuronal nitric oxide synthase (nNOS) than endothelial NOS (eNOS) or inducible NOS (iNOS), could be useful in the treatment of cerebral ischemia and other neurodegenerative diseases. We recently described the synthesis of a series of imidazole derivatives. Among them N-(4-nitrophenacyl) imidazole (A) and N-(4-nitrophenacyl)-2-methyl-imidazole (B) were considered selective nNOS inhibitors. In the present study the action mechanism of compounds A and B was analyzed. Spectral changes observed in the presence of compound A indicate that this inhibitor exerts its effect without interaction with heme iron. Moreover compounds A and B, inhibit nNOS “noncompetitively” versus arginine, but “competitively” versus BH4.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The aminobenzothiophenes mentioned in the title (III) are synthesized from the bromonitrobenzothiophene (I) and the amines (II).