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Posted: Feb 10, 2015
Benzodiazepines, the ring of power
(Nanowerk News) If anything characterizes the efforts of the research community in the research and development of new drugs is that this requires multiple approaches from different disciplines of knowledge without which it would be possible to obtain new medicines.
From chemical point of view, one of the strategies that best result has given the scientific community is the application of the concept “privileged structure”, also referred to as privileged rings. This term refers to the structural properties of certain cyclic compounds, whose components are at least one element other than carbon; this makes them heterocyclic rings.
The way to the bottom: the value of the structure
Privileged structures have played a decisive role in the field of drug discovery. With its ability to modulate diverse biological targets, such heterocyclic rings have been able to provide a considerable number of drugs to treat diseases differ widely, partly because their use is generally associated with a low incidence of adverse effects. In addition, the privileged rings facilitate the rapid rational advances within drug discovery programs, an increasingly complex, competitive and expensive process.
Benzodiazepines are the archetypal privileged structures; its introduction in clinical practice revolutionized the therapy of psychiatric disorders, particularly the treatment of anxiety, insomnia and epilepsy. With over 30 benzodiazepines in clinical use, no other privileged ring has contributed to the therapeutic arsenal, resulting in numerous commercial drugs in widespread use among which are some well-known as Valium®, Orfidal® , Lexatin® or Trankimazin®. However, the the real exceptionality of benzodiazepine ring lies in the diversity of its therapeutic applications, highlighting not only its effects in psychiatric diseases, but also its use as muscle and adjuvant relaxing in dental anaesthesia or endoscopic.
Exploring new therapeutic avenues
The structural manipulation of the benzodiazepine ring in the laboratory enabled to eliminate its central nervous system activity; thus opening the field to the development of new drugs to treat completely different diseases, including cancer, inflammation, malaria, circulatory disorders or autoimmune diseases.
Now a study developed by researchers at CiQUS and the Faculty of Pharmacy of the USC describes a conceptually novel synthetic approach that provides benzodiazepine collections representative of previously unexplored diversity spaces, particularly skeletal, functional and stereochemical diversity. The project, leaded by Professor Eddy Sotelo, developed an efficient, fast and environmentally-friendly synthetic strategy, fitting some of the key Green Chemistry principles; thus documenting the reconciliation of molecular complexity and experimental simplicity.
The new method, published in the Journal of Organic Chemistry ("Integrated Ugi-Based Assembly of Functionally, Skeletally, and Stereochemically Diverse 1,4-Benzodiazepin-2-ones"), has provided more than 80 representative molecules, whose structural distinctiveness has been validated during its pharmacological evaluation. In addition to compounds with excellent anxiolytic action, and after the required structural manipulation to eliminate central nervous system effects, researchers identified some new hit structures acting on validated therapeutic targets for diseases such as diabetes, asthma or tuberculosis.
The results of this project, which also involved researchers from the universities of Vigo and Valencia, represent a milestone of Professor Sotelo’s group, which focuses on the development of multicomponent synthetic strategies to accelerate the generation and optimization of drug candidates, especially those aimed at diseases such as glaucoma, Parkinson's disease, asthma or cancer.