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  • Adenosine is an endogenous nucleoside that plays

    2024-05-23

    Adenosine is an endogenous nucleoside that plays pivotal roles in different physiological and pathophysiological processes by triggering specific cell-surface receptors both in the amc 7 and in the periphery. The adenosine receptors (ARs) are four different subtypes of G protein-coupled receptors (GPCRs) classified as A, A, A and A on the basis of their tissue localization, respective coupling to adenylate cyclase (AC), and specific pharmacological criteria., ARs are widely distributed in the body and are expressed with different density in the various tissues. The classical transduction intracellular pathways associated with AR stimulation are inhibition, via G protein (A and A subtypes), or activation, via G protein (A and A receptors), of adenylate cyclase (AC). More recently, other second messenger systems have been described as relevant for AR signaling., , Due to the widespread distribution of ARs, and to the ubiquity of the natural ligand adenosine, selective modulation of each receptor subtype could be exploited for therapeutic advantages. ARs have recently been recognized as novel and potential drug targets for therapeutic intervention in many pathological conditions such as cardiac and cerebral ischemia, asthma, renal failure, CNS disorders, inflammatory and neurodegenerative diseases. Over the years, many ligands, agonists as well as antagonists, have been identified for the ARs that, in turn, have been extensively characterized. In fact, a large number of selective AR antagonists belonging to different chemical classes have been developed, leading to the identification of several recurring structural features to define the affinity or efficacy of a ligand for the target receptor subtype., Although the considerable number of AR ligands have been discovered and clinically evaluated, only a few have been approved by the FDA. Moreover, some phase I studies were interrupted due to low absorption, short half-life or other correlated limitations., Thus, recent attention has focused on preliminary detection of pharmacokinetic (ADME) properties whose optimization should be pursued together with the improvement of potency., For all these reasons, there is a great deal of interest in the search for new chemical entities (NCEs) using privileged structures as a support approach. In fact, the use of privileged framework in drug discovery has proven to be an effective strategy for the generation of novel leads and optimization processes. The pyridazin-3(2H)-one has been recognized as a privileged structure for the design of novel compounds with potential pharmacological interest. In particular, fruitful medicinal chemistry approaches using this core skeleton have been performed in the field of AR ligands allowing discovery of some NCEs (series –, A)., , Moreover, it is important to mention that the pyridazinone moiety is also present in both agonists and antagonists of ARs as a versatile substituent in critical side chains (series –, B)., , With this in mind, we have embarked on a project focused on the discovery of NCEs that incorporate the pyridazin-3(2H)-one substructure. In the past, we identified the phthalazin-1(2H)-one scaffold as a new decorable core skeleton for the design of potent and selective human (h) AAR antagonists. These studies were a part of a wider research program focused on the development of new potent and selective adenosine receptor ligands belonging to different chemical classes., , , , , , , , , , Recently, our attention has been devoted to the thieno[2,3-]pyridazin-5(4H)-one scaffold that, to our knowledge, has never been functionalized for the design of AR ligands. Moreover, this scaffold seems to be an attractive synthetic building block to perform a wide array of structural modifications, allowing an easy synthesis of potential AR ligands characterized by good yields. Thus, we have started a pilot study to investigate the versatility of the thieno[2,3-]pyridazin-5(4H)-one core as the basis of new compounds binding the ARs. The currently reported thienopyridazinone derivatives (compounds –, C) possess, in addition to a bicyclic core typical of AR ligands, structural similarities with a series of thieno[3,2-]pyrimidines (series , C) reported by Gillespie et al. as A AR antagonists. A partial overlapping of the critical features can be found also for the series of differently anellated thienopyridazinones reported by Ferguson et al. (series , A) as AAR antagonists able to recognize the receptor allosteric site too. The R, R and R positions of the thieno[2,3-]pyridazin-5(4H)-one framework were explored by designing compounds –.