Combinatorial Library Synthesis and Biological Evaluation of Pyrazolo[4,3‐e][1,4]diazepine as a Potential Privileged Structure

Abstract

A privileged structure: A library of tetrahydro‐1,4‐pyrazolo‐diazepin‐8(2H)‐ones was designed and synthesized to probe the privileged nature of the scaffold. The design strategy included mimicking the three‐dimensional conformations of β‐turn peptides. Screening against P2X7R, BACE‐1, and MC4R gave several hit compounds for each target. The results suggest that pyrazolodiazepin‐8‐one may represent a potential privileged scaffold.magnified image

Privileged Structures - Dream or Reality: Preferential Organization of Azanaphthalene Scaffold

“…There are several examples of privileged scaffold library synthesis, e.g. based on a 2-arylindole that resulted in the discovery of potent ligands for a variety of G-protein coupled receptors [108], purine derivatives [109] or tetrahydro-1,4-pyrazolodiazepin-8(2H)-ones [110]. In general, PS should typically exhibit good drug-like properties, which in turn lead to additional drug-like compound libraries and leads.…”

Privileged scaffolds for library design and drug discovery

“…One recent example of such a study was provided by Kim and co-workers, who created a library of compounds around the 1,4-pyrazolodiazepin-8-one structure (which can be found in Table 4) with the goal of using these diazepines to closely mimic the β-turn structure of a number of peptides [33]. Globally, this scaffold allowed for the introduction three points of diversification while still allowing for compounds to maintain the necessary triangular geometries of such peptide turns.…”

Selective C-Acylation of 2-Aminoimidazo[1,2-a]pyridine: Application to the Synthesis of Imidazopyridine-Fused [1,3]Diazepinones

“…The first prototype of such structures, which led to many clinical and commercial successes, was the diazepine scaffold. , Since the discovery of the benzodiazepine family as central nervous system depressants, many synthetic derivatives, displaying a wide pharmacological spectrum including antithrombotic, antibiotic, and antitumor , properties, have been extensively developed. Much attention has been paid to the replacement of the fused benzene ring by a heterocyclic ring system such as thiophene, , pyrazole, , imidazole, pyrrole, − indole, , furan, etc. Among the different classes of diazepines, the [1,3]diazepines have been studied to a minor extent although their derivatives are also of interest due to their ability to bind multiple therapeutic targets.…”