Novel benzodiazepine receptor partial agonists: oxadiazolylimidazobenzodiazepines

Abstract

The synthesis and biochemical evaluation of a series of oxadiazole derivatives of imidazobenzodiazepines related to the benzodiazepine antagonist Ro 15-1788 (2a) are reported. Although the oxadiazole ring is seen as an isosteric replacement for the ester linkage, significant differences in structure-activity trends were observed. Specifically, oxadiazoles 9-12 invariably had increased receptor efficacy (as witnessed by measurements of the GABA shift) relative to the corresponding ester. Additionally, and in direct contrast to the classical agonists such as diazepam, affinity for the benzodiazepine receptor was enhanced by a 7- rather than 8-halo substituent. The results are discussed in terms of a six-point receptor-binding model originally based on the X-ray structure of 2a. For comparison, the crystal structures of two representative oxadiazole derivatives, 10h and 12o, having a 6-oxo and 6-phenyl group, respectively, were determined and the data incorporated into a modified binding model to account for the greater efficacy of these compounds. It is concluded that the antagonist behavior of 2a relies upon the hydrogen-bond-acceptor properties of the ester carbonyl oxygen whereas for the oxadiazole series this site is localized at the imidazole nitrogen.

Metabolism of [14C]GSK977779 in Rats and Its Implication with the Observed Covalent Binding

“…Further investigations regarding the identity of the covalently bound metabolite could be performed using enzyme digestion of the isolated protein adduct or matrix-assisted laser desorption/ionization MS to analyze the plasma protein-GSK977779-related adduct. This research would be of broad interest to the pharmaceutical community because the oxadiazole ring is commonly used in place of ester linkages in the structures of xenobiotics (Watjen et al, 1989).…”

Oxadiazoles

“…13.3.6 1,2,4-Oxadiazoles in Medicine 1,2,4-Oxadiazole ring occurs widely in biologically active synthetic compounds, and is often used in drug discovery as a hydrolysis-resisting bioisosteric replacement for amide or ester functionalities [283] because of its electronic properties. Its derivatives can be found in a vast number of compounds exerting biological activity, such as ligands of benzodiazepine receptors [284,285], anti-inflammatory agents [131,199,234], antiviral agents [283], inhibitors of protein tyrosine phosphatases [286], agonists of muscarinic receptors [287], inhibitors of Src SH2 [183], antagonists of histamine H 3 -receptors [288], integrin receptor antagonists [200], angiotensin II receptor antagonists [289], and HIV-1 reverse transcriptase inhibitors [290]. 1,2,4-Oxadiazole moieties have been used in the design of dipeptidomimetics as peptide building blocks [184a,b].…”

Green Approach Towards Synthesis of 3-Substituted-5-Carbonylmetyl-1,2,4-Oxadiazoles Without Any Solvent and Catalyst via Transamidoximation.

“…The construction of new heterocyclic scaffold derivatives which illustrate pharmacological and biological significance stands for a most important assignment in synthetic and medicinal chemistry. 1,2,4-Oxadiazoles are amazing classes of N-heterocyclic compounds showing their broad spectrum of valuable promising biological activities, such as muscarinic agonists, 4 serotoninergic (5-HT3) antagonists, 5 benzodiazepine receptor agonists, 6 dopamine ligands, 7 inhibitors of monoamine oxidase, 8 sphingosine-1-phosphate-1 (S1P 1 ) receptor agonist 9 can say that 1,2,4-oxaziazole core unit have been explored in past years. 1,2,4-Oxadiazoles have often been used as hydrolysis-resisting bioisosteric replacements for esters and amides 10 and as dipeptide mimetics 11 Bearing in mind the noteworthy relevancies in the fields of medicinal, biological and synthetic organic chemistry, there has been marvelous curiosity in developing efficient procedures for the synthesis of 1,2,4-oxadiazoles and quite number of synthetic procedures have been accounted in the literature for the synthesis of 1,2,4-oxadiazoles derivatives, which include the reaction of amidoxime with activated carboxylic acid derivatives such as acid chlorides, 12 fluorides, 13 anhydrides (BOP-Cl), 14 or active esters 15 using coupling reagents like, DCC, 16 DIC/HOBt, 17 TBTU, 18 CDI.…”