Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta.

Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties as well as neuroprotective effects in cellular and animal models of Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis.

Pharmacological Characterization of P626, a Novel Dual Adenosine A/A Receptor Antagonist, on Synaptic Plasticity and during an Ischemic-like Insult in CA1 Rat Hippocampus.

In recent years, the use of multi-target compounds has become an increasingly pursued strategy to treat complex pathologies, including cerebral ischemia. Adenosine and its receptors (AAR, AAR, AAR, AAR) are known to play a crucial role in synaptic transmission either in normoxic or ischemic-like conditions. Previous data demonstrate that the selective antagonism of AAR or AAR delays anoxic depolarization (AD) appearance, an unequivocal sign of neuronal injury induced by a severe oxygen-glucose deprivation (OGD) insult in the hippocampus.

"Dual Anta-Inhibitors" of the A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies.

Based on a screening of a chemical library of A adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1δ) and to bind adenosine receptors (ARs). Some derivatives, here called "dual anta-inhibitors", demonstrated good CK1δ inhibitory activity combined with a high binding affinity, especially for the AAR. The -methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (, IC = 0.

4-Heteroaryl Substituted Amino-3,5-Dicyanopyridines as New Adenosine Receptor Ligands: Novel Insights on Structure-Activity Relationships and Perspectives.

A new set of amino-3,5-dicyanopyridines was synthesized and biologically evaluated at the adenosine receptors (ARs). This chemical class is particularly versatile, as small structural modifications can influence not only affinity and selectivity, but also the pharmacological profile. Thus, in order to deepen the structure-activity relationships (SARs) of this series, different substituents were evaluated at the diverse positions on the dicyanopyridine scaffold.

Casein Kinase 1δ Inhibitors as Promising Therapeutic Agents for Neurodegenerative Disorders.

Casein kinase 1 (CK1) belongs to the serine-threonine kinase family and is expressed in all eukaryotic organisms. At least six human isoforms of CK1 (termed α, γ1-3, δ and ε) have been cloned and characterized. CK1δ isoform modulates several physiological processes, including DNA damage repair, circadian rhythm, cellular proliferation and apoptosis.

A Adenosine Receptor Antagonists and their Potential in Neurological Disorders.

Endogenous nucleoside adenosine modulates a number of physiological effects through interaction with P1 purinergic receptors. All of them are G protein-coupled receptors, and, to date, four subtypes have been characterized and named A, A, A, and A. In recent years, adenosine receptors, particularly the A subtype, have become attractive targets for the treatment of several neurodegenerative disorders, known to involve neuroinflammation, like Parkinson's and Alzheimer's diseases, multiple sclerosis, and neuropsychiatric conditions.

Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives with High Affinity for Both the Adenosine A and A Receptors, and Efficacy in Animal Models of Depression.

New compounds with a 7-amino-2-arylmethyl-thiazolo[5,4-d]pyrimidine structure were synthesized and evaluated in vitro for their affinity and/or potency at the human (h) A, hA, hA, and hA adenosine receptors (ARs). Several compounds (, -, , , ) were characterized by nanomolar and subnanomolar binding affinities for the hA and the hA AR, respectively. Results of molecular docking studies supported the in vitro results.

Special Issue "Adenosine Receptors as Attractive Targets in Human Diseases".

The idea of promoting this Special Issue arises from the desire to witness the multidisciplinary efforts that are currently in progress to provide new insights into the pathophysiological role of adenosine [...

Piperazine- and Piperidine-Containing Thiazolo[5,4-]pyrimidine Derivatives as New Potent and Selective Adenosine A Receptor Inverse Agonists.

The therapeutic use of A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A AR antagonists to avoid both immunoescaping of tumor cells and tumor development is well documented. Herein, we report on the synthesis and biological evaluation of a new set of piperazine- and piperidine- containing 7-amino-2-(furan-2-yl)thiazolo[5,4-]pyrimidine derivatives designed as human A AR antagonists/inverse agonists.

Discovery of first-in-class multi-target adenosine A receptor antagonists-carbonic anhydrase IX and XII inhibitors. 8-Amino-6-aryl-2-phenyl-1,2,4-triazolo [4,3-a]pyrazin-3-one derivatives as new potential antitumor agents.

This paper describes identification of the first-in-class multi-target adenosine A receptor antagonists-carbonic anhydrase (CA) IX and XII inhibitors, as new potential antitumor agents. To obtain the multi-acting ligands, the 8-amino-2,6-diphenyltriazolo[4,3-a]pyrazin-3-one, a potent adenosine hA receptor (AR) antagonist, was taken as lead compound. To address activity against the tumor-associated CA isoforms, it was modified by introduction of different substituents (OH, COOH, CONHOH, SONH) on the 6-phenyl ring or on a phenyl pendant connected to the former through different spacers.

Adenosine A receptors inhibit K currents and cell differentiation in cultured oligodendrocyte precursor cells and modulate sphingosine-1-phosphate signaling pathway.

Oligodendrocytes are the only myelinating cells in the brain and differentiate from their progenitors (OPCs) throughout adult life. However, this process fails in demyelinating pathologies. Adenosine is emerging as an important player in OPC differentiation and we recently demonstrated that adenosine A receptors inhibit cell maturation by reducing voltage-dependent K currents.

New 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives. Evaluation of different moieties on the 6-aryl ring to obtain potent and selective human A adenosine receptor antagonists.

In this work, further structural investigations on the 8-amino-2-phenyl-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-one series were carried out to achieve potent and selective human A adenosine receptor (AR) antagonists. Different ether and amide moieties were attached at the para-position of the 6-phenyl ring, thus leading to compounds 1-9 and 10-18, respectively. Most of these moieties contained terminal basic rings (pyrrolidine, morpholine, piperidine and substituted piperazines) which were thought to confer good physicochemical and drug-like properties.

Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors Ranging from Pan Ligands to Combined A/A Partial Agonists.

The amino-3,5-dicyanopyridine derivatives belong to an intriguing series of adenosine receptor (AR) ligands that has been developed by both academic researchers and industry. Indeed, the studies carried out to date underline the versatility of the dicyanopyridine scaffold to obtain AR ligands with not only a wide range of affinities but also with diverse degrees of efficacies at the different ARs. These observations prompted us to investigate on the structure-activity relationships (SARs) of this series leading to important previously reported results.

Antioxidant-Conjugated 1,2,4-Triazolo[4,3-]pyrazin-3-one Derivatives: Highly Potent and Selective Human A Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain.

New 8-amino-6-aryl-1,2,4-triazolo[4,3-]pyrazin-3-ones were designed to obtain dual antioxidant-human A adenosine receptor (hA AR) antagonists. Two sets of compounds were synthesized, the first featuring phenol rings at the 6-position, the second bearing the lipoyl and 4-hydroxy-3,5-di-but-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines () were potent and selective hA AR antagonists ( = 0.

Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity.

A new series of amino-3,5-dicyanopyridines () was synthesized and biologically evaluated in order to further investigate the potential of this scaffold to obtain adenosine receptor (AR) ligands. In general, the modifications performed have led to compounds having high to good human (h) AAR affinity and an inverse agonist profile. While most of the compounds are hAAR-selective, some derivatives behave as mixed hAAR inverse agonists/A and A AR antagonists.

Functional characterization of a novel adenosine A receptor agonist on short-term plasticity and synaptic inhibition during oxygen and glucose deprivation in the rat CA1 hippocampus.

Adenosine is an endogenous neuromodulator exerting its biological functions via four receptor subtypes, A, A, A, and A. A receptors (ARs) are expressed at hippocampal level where they are known to inhibit paired pulse facilitation (PPF), whose reduction reflects an increase in presynaptic glutamate release. The effect of ARs on PPF is known to be sensitive not only to AR blockade but also to the AR antagonist DPCPX, indicating that it involves AR activation.

Novel 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives as potent human adenosine A and A receptor antagonists. Evaluation of their protective effect against β-amyloid-induced neurotoxicity in SH-SY5Y cells.

In this work, an enlarged series of 1,2,4-triazolo[4,3-a]pyrazin-3-ones was designed to target the human (h) A adenosine receptor (AR) or both hA and hA ARs. The novel 8-amino-1,2,4-triazolopyrazin-3-one derivatives 1-25 featured a phenyl or a benzyl pendant at position 2 while different aryl/heteroaryl substituents were placed at position 6. Two compounds (8 and 10) endowed with high affinity (K = 7.

Novel human adenosine receptor antagonists based on the 7-amino-thiazolo[5,4-d]pyrimidine scaffold. Structural investigations at the 2-, 5- and 7-positions to enhance affinity and tune selectivity.

This paper describes the synthesis of novel 7-amino-thiazolo[5,4-d]pyrimidines bearing different substituents at positions 2, 5 and 7 of the thiazolopyrimidine scaffold. The synthesized compounds 2-27 were evaluated in radioligand binding (A, A and A) and adenylyl cyclase activity (A and A) assays, in order to evaluate their affinity and potency at human adenosine receptor subtypes. The current study allowed us to support that affinity and selectivity of 7-amino-thiazolo[5,4-d]pyrimidine derivatives towards the adenosine receptor subtypes can be modulated by the nature of the groups attached at positions 2, 5 and 7 of the bicyclic scaffold.

Structure-activity relationship studies and pharmacological characterization of N-heteroarylalkyl-substituted-2-(2-furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine-based derivatives as inverse agonists at human A adenosine receptor.

This paper describes the synthesis and characterization of N-(hetero)arylalkyl-substituted-thiazolo [5,4-d]pyrimidine-5,7-diamine derivatives (4-19) as novel human (h) A adenosine receptor (AR) inverse agonists. Competition binding and cyclic AMP assays indicate that the examined compounds behave as hA AR inverse agonists showing binding affinity values in the nanomolar or subnanomolar range. Notably, compounds 4, 5, 6 and 11 showed two affinity values for the hA ARs with the highest (KH) falling in the femtomolar range and the lowest (KL) of the nanomolar order.

Identification of novel thiazolo[5,4-d]pyrimidine derivatives as human A and A adenosine receptor antagonists/inverse agonists.

In this study a new set of thiazolo[5,4-d]pyrimidine derivatives was synthesized. These derivatives bear different substituents at positions 2 and 5 of the thiazolopyrimidine core while maintaining a free amino group at position-7. The new compounds were tested for their affinity and potency at human (h) A, A, A and A adenosine receptors expressed in CHO cells.

Development of novel pyridazinone-based adenosine receptor ligands.

With the aim of finding new adenosine receptor (AR) ligands, a preliminary investigation focusing on the thieno[2,3-d]pyridazin-5(4H)-one scaffold was undertaken. The synthesized compounds 1-11 were evaluated for their binding at hA, hA and hA ARs and efficacy at hA subtype in order to determine the affinity at the human adenosine receptor subtypes. Small structural changes on this scaffold highly influenced affinity; compound 5 (5-ethyl-7-(thiazol-2-yl)thieno[2,3-d]pyridazin-4(5H)-one) emerged as the best of this series.

The aminopyridine-3,5-dicarbonitrile core for the design of new non-nucleoside-like agonists of the human adenosine A receptor.

A new series of amino-3,5-dicyanopyridines (3-28) as analogues of the adenosine hA receptor agonist BAY60-6583 (compound 1) was synthesized. All the compounds that interact with the hA adenosine receptor display EC values in the range 9-350 nM behaving as partial agonists, with the only exception being the 2-{[4-(4-acetamidophenyl)-6-amino-3,5-dicyanopyridin-2-yl]thio}acetamide (8) which shows a full agonist profile. Moreover, the 2-[(1H-imidazol-2-yl)methylthio)]-6-amino-4-(4-cyclopropylmethoxy-phenyl)pyridine-3,5-dicarbonitrile (15) turns out to be 3-fold more active than 1 although less selective.

Structural investigations on coumarins leading to chromeno[4,3-c]pyrazol-4-ones and pyrano[4,3-c]pyrazol-4-ones: New scaffolds for the design of the tumor-associated carbonic anhydrase isoforms IX and XII.

Human carbonic anhydrases (hCAs, EC 4.2.1.