397 research outputs found
New Frontiers in Selective Human MAO-B Inhibitors
No full textAccumulating evidence shows a relationship between the human MAO-B (hMAO-B) enzyme and neuropsychiatric/degenerative disorder, personality traits, type II alcoholism, borderline personality disorders, aggressiveness and violence in crime, obsessive-compulsive disorder, depression, suicide, schizophrenia, anorexia nervosa, migraine, dementia, and PD. Thus, MAO-B represents an attractive target for the treatment of a number of human diseases. The discovery, development, and therapeutic use of drugs that inhibit MAO-B are major challenges for future therapy. Various compounds and drugs that selectively target this isoform have been discovered recently. These agents are synthetic compounds or natural products and their analogues, including chalcones, pyrazoles, chromones, coumarins, xanthines, isatin derivatives, thiazolidin-diones, (thiazol-2-yl)hydrazones, and analogues of marketed drugs. Despite considerable efforts in understanding the binding interaction with specific substrates or inhibitors, structural information available for the rational design of new hMAO-B inhibitors remains unsatisfactory. Therefore, the quest for novel, potent, and selective hMAO-B inhibitors remains of high interest
Sintesi e attività inibitoria selettiva sull’isoforma B delle MAO di derivati alchiliden-(4-ariltiazol-2-il)idrazonici
No full textNon-classical and selective carbonic anhydrase inhibitors: new scaffolds in the limelight?
No full textSelective carbonic anhydrase IX inhibitors based on coumarin scaffold as promising antimetastatic agents: WO2012070024
No full textSynthesis and biological evaluation of a new thiazole derivative, inducing histone hypoacetylation and apoptosis in human leukemia cells
No full textFocusing on new monoamine oxidase inhibitors
No full textImportance of the field: Monoamine oxidase (MAO) plays a significant role in the control of intracellular concentration of monoaminergic neurotransmitters or neuromodulators and dietary amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional and other brain functions. Furthermore, modulators of neurotransmitters exert pleiotropic effects on mental and cognitive functions. The by-products of MAO-mediated reactions include several chemical species with neurotoxic potential. It is widely speculated that prolonged or excessive activity of these enzymes may be conducive to mitochondrial damages and neurodegenerative disturbances. In keeping with these premises, the development of human MAO inhibitors has led to important breakthroughs in the therapy of several neuropsychiatric disorders. Areas covered in this review: This review highlights the recent MAO inhibitors related patents published from July 2005 to December 2009. It also reports on new associations of already known MAO inhibitors with other drugs, innovative therapeutic targets, MAO inhibitors obtained by plants extraction, alternative administration routes and synthetic processes. What the reader will gain: The reader will gain an overview of the main structures being investigated and their biological activities. Take home message: Several of these MAO inhibitors appear promising for further clinical development
Mechanisms of action of carbonic anhydrase inhibitors: compounds that bind “out of the binding site” and compounds with an unknown mechanism of action
No full textSo far, the design of human carbonic anhydrase (CA) inhibitors has been easily driven by the introduction of specific Zinc Binding Groups (ZBGs) (primary and secondary sulfonamides and their bioisosteres, dithiocarbamates, phosphonates, hydroxamic acids, and so on), which directly or indirectly block the enzyme-mediated catalytic CO2 hydration. All these inhibitors have been elegantly characterized by X-ray diffraction studies of hCA II-inhibitor adducts. The results led to the discovery of several drug candidates potent and selective for clinical purposes. Conversely, the most exciting innovation was the proposal of an alternative mechanism of inhibition targeting the proton shuttle His64 out of the binding site. Moreover, new chemotypes without the above described moieties are emerging as endowed with an unknown mechanism of interaction. New scenarios could be observed within these scaffold to finely modulate CA activity
Enzyme-mediated activation of prodrugs
No full textThe development of potent drugs is always a challenging task and is often complicated by the number of pharmacokinetic and formulation limitations they suffer from. In addition, selectivity issues and targeting purposes make the regulatory approval a difficult-to-gain achievement. In this context, prodrugs strategy is widely employed and successful, especially, when a rational design is performed. Thus prodrugs are generated by introducing specific moieties or masking of already present chemical groups in the drug compounds in order to make them inactive or less active and allow a selective in vivo conversion into the corresponding active metabolites. The bioactivation process is mediated by chemical reactions due to the tissue microenvironment of the absorption or active site, e.g., the pH—acidic in the stomach or basic in the intestines—or reductive—in hypoxic cancers—or by the mediation of specific enzymes or classes of enzymes. Herein, we present an overview of enzymes involved in prodrugs activation, discussed according to the international enzyme classification (EC). Also, representative examples from the clinics are reported
Innovative Extraction Techniques and Hyphenated Instrument Configuration for Complex Matrices Analysis
No full textn/
Epigenetic modulation of PGC-1α activity by GCN5 inhibitors: WO2010007085
No full textThe transcriptional peroxisome proliferator-activated receptor γ (PPARγ) co-activator PGC-1α plays a central role in the regulation of cellular energy metabolism. Among the wide range of its activities, PGC-1α controls mitochondrial biogenesis and function and is one of the main factors involved in hormonal and nutrient regulation of hepatic gluconeogenesis. PGC-1α is present in a multiprotein complex, and its activity can also be modulated through epigenetic modifications. In particular, it is directly acetylated by the HAT enzyme general control nonderepressible 5 (GCN5), resulting in a transcriptionally inactive protein that relocalizes from promoter regions to nuclear foci, whereas it is deacetylated by SIRT1 at multiple lysine sites, with a subsequent increase in its activity leading to induction of liver gluconeogenic gene transcription. Thus, both GCN5 and SIRT1 may be pharmacological targets to regulate the activity of PGC-1α, providing a potential treatment for metabolic disorders in which hepatic glucose output is altered
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