Current Medicinal Chemistry - Volume 13, Issue 30, 2006

This review summarizes the current tendencies observed in the past 5 years in the development of A1 and A2A adenosine receptor antagonists performed in various academia and industry. A1 and A2A AR antagonists are as well xanthines as heteroaromatic derivatives and are most commonly 6:5 fused heteroatomic compounds. Among xanthine-based compounds, some common features could be pointed out. The recent A1 AR ligands which show good biological profile, possess long alkyl chains in position 1 and 3 as well as bulky C(8)- substituent, while A2A AR antagonists with a high A2A AR affinity are C(8)-styryl substituted with N(1)- alkyl/alkynyl moiety or fused tricyclic xanthines possessing heteroatom(s) in the third cycle. The research in the field of heteroaromatic A1 and A2A ARs antagonists impressively has a wide range. Ligands are as well non-fused monocyclic substituted compounds as fused bi- and tricyclic derivatives with the nitrogen, oxygen and sulfur heteroatoms. Most often, adenosine A1 receptor non-xanthine antagonists are adenine-based, having substituted amino group and variable nitrogen atoms positions in the molecules. A2A AR ligands show good affinity when furanyl function, which is crucial for binding, is present in the fused bicyclic and tricyclic analogs. Moreover, tricyclic nitrogen containing antagonists in order to be active, frequently possess long-alkylphenyl moiety.

Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O2-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the arginine moiety in numerous peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors, factor VIIa inhibitors, integrin receptor antagonists, nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability.

Morbidity and mortality of chronic liver disease are primarily caused by liver cirrhosis and portal hypertension, both of them secondary disorders of progressive liver fibrosis. The main fibrogenic cell type in the liver, the hepatic stellate cell (HSC), is activated and stimulated by several factors, among which the renin-angiotensin-aldosterone system (RAAS) plays a major role. Angiotensin II induces various profibrotic pathways via the angiotensin II receptor type 1 (AT1 receptor) not only in heart and kidney, but also in liver tissue. Stimulation of the AT1 receptor promotes the transformation of the quiescent HSC into the myofibroblast like activated HSC and the synthesis of transforming growth factor- 1 (TGF-7bgr;), the major profibrotic cytokine in the liver. In addition, aldosterone has been suggested to induce profibrotic effects in chronic heart and liver disease. This review focuses on the concept that inhibitors of the RAAS retard or even reverse liver fibrosis and reduce portal hypertension. Angiotensin converting enzyme (ACE) inhibitors, AT1 receptor antagonists, and aldosterone antagonists have been demonstrated to reduce the proliferation of HSC, to decrease the synthesis of profibrotic molecules, and to have the potential to improve liver fibrosis. However, side-effects such as systemic hypotension may impair the clinical application of RAAS inhibitors in patients with liver cirrhosis and portal hypertension. Also, efficacy may be limited by the downregulation of AT1 receptors in advanced fibrosis, which has been observed in animal and human studies. Randomized clinical studies are essential to evaluate, whether this approach is beneficial in patients with chronic liver disease and progressive fibrosis.

Eight novel 2-(2'-cyclopentyl)- and 2-(2'-cyclohexyl) substituted 1-naphthol derivatives were synthesized in good yield starting from 1-hydroxy-2-naphthoic acid. Two of them, 2-((1- (hydroxymethyl)cyclopentyl)methyl)naphthalene-1-ol (8) and 2-((1-(hydroxymethyl)cyclohexyl)methyl)- naphthalene-1-ol (9) showed anticyclooxygenase activity on COX-2 with IC50 values of 19.90 μM and 7.77 μM, respectively and 9 also inhibited COX-1 (5.55 μM), while the other six were inactive on both isozymes. Molecular docking experiments indicated that the orientation of the active naphthols is different from that of the inactive ones. Two evidences playing important roles for the inhibition by the active compounds, are 1) C- 1 and C-3' hydroxyl groups formed hydrogen bonds with COX-2/COX-1 Val523/Ile523 and Arg120, respectively, 2) hydrogen at C-5 of the naphthalene nucleus was attracted rather close to the phenolic group of Tyr385 due to van der Waals interaction.

Phosphonated nucleosides represent a promising alternative in the improvement of the biological activity of nucleoside analogues in antiviral and anticancer chemotherapy. The basic concept, the chemistry, the different structural modifications and their effects on the antiviral potency will be discussed in this review.

The new generation of biologically active compounds developed during the 20th century relied on knowledge of enzymology and protein structure, and were based initially, on the understanding that proteinprotein and small molecule-protein interactions occurred through a lock-and-key mechanism. Later, evidence suggested that this mechanism was usually followed by a conformational change, known as induced fit. Recent studies on protein dynamics, mainly by nuclear magnetic resonance (NMR) relaxation measurements, have shown that proteins are not structured in a unique conformation. Rather, they frequently have regions of conformational diversity. In the present review we will discuss a novel view of binding, put forward in by several research groups in the last 5 to 10 years. In the free state, protein regions displaying conformational diversity exhibit equilibria among pre-existing conformations. In the presence of a ligand, one of these conformations is stabilized, so that the ligand does not need to induce a new conformation. Upon ligand binding there is a population shift toward the bound conformational state. Conformational diversity of binding sites of several proteins has been measured and has important practical as well as thermodynamical consequences: binding sites can be mapped without prior knowledge of the ligand and also evolution of binding sites depends mostly on the free state, occurring at least partially independently of the ligand.

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder with a heterogeneous clinical picture and a variable rate of progression. PD is characterized by degeneration of the pigmented neuromelanin bearing cells of the pars compacta of the substantia nigra that leads to a severe dopaminergic denervation of the striatum. Current treatments for PD rely on dopamine replacement therapy, most commonly with the dopamine precursor levodopa. Despite the many recent advances in the symptomatic treatment of PD, there is still no realistic prospect for a cure. In recent years, new data support the idea of a relevant role for the cannabinoid system in PD. As cannabinoids have neuroprotective properties, they have been proposed as potentially useful neuroprotective substances in PD, as well as to alleviate some symptoms in specific circumstances (i.e. parkinsonian tremor associated with overactivity to the subthalamic nucleus; levodopainduced dyskinesia). By contrast, CB1 receptor antagonists might be useful to reduce bradykinesia in patients refractory to classic levodopa treatment. The present article will review all data about the relationship between PD and the cannabinoid system including: i) the usefulness of cannabinoid-related compounds to alleviate some PD symptoms; ii) that cannabinoid-based compounds might provide protection against the progression of neuronal injury characteristic of this disease; iii) the influence of cannabinoids on local inflammatory events associated with the pathogenesis in PD. Collectively, all these evidence support that the management of the cannabinoid system might represent a new approach to the treatment of PD.

S-100 protein, described initially by Moore, constitutes a large family of at least 20 proteins with calcium binding ability. It is found as homo- or hetero-dimers of two different subunits (A and B). Types S-100AB and S-100BB are described as S-100B protein and are shown to be highly specific for nervous tissue. It is present in the cytosol of glial and Schwann cells, and also in adipocytes and chondrocytes, although in very low concentrations in the latter two. The role of protein S-100B is not yet fully understood. It is suggested that it has intracellular and extracellular neurotropic as well as neurotoxic function. At nanomolar levels, S-100B stimulates neurite outgrowth and enhances survival of neurons. However, at micromolar levels it stimulates the expression of inflammatory cytokines and induces apoptosis. Recently, serum S-100B protein has been proved to be an attractive surrogate marker of primary severe brain injury and secondary insults. It can be measured in the arterial and venous serum; it is not affected by haemolysis and remains stable for several hours without the need for immediate analysis. Its short half-life makes measurements crucial in the emergency and intensive care settings. This review summarises published findings on S-100B regarding its role as a serum biochemical marker of brain injury, i.e., after severe, moderate or mild neuro-trauma, subarachnoid haemorrhage, thrombo-embolic stroke, cerebral ischaemia and brain tumours, as well as extracranial trauma, neurodegenerative and psychiatric disorders.