Search

Glucocorticoids (GC) are widely used in therapy for their many pharmacological properties including antiinflammatory and immunosuppressive actions. However, their use over long periods is hampered by a number of severe side effects. Given the biological properties of nitric oxide (NO) and previous experience with nonsteroidal antiinflammatory agents, we synthesized new chemical entities combining both NO and GC properties. Here we report the synthesis of nitro esters of prednisolone obtained through the esterification, with different linkers, on the hydroxy group at C-21 position of the corticosteroid structure. The alkyl chain, as of the nitrooxy derivative (2), or aromatic linkers, as of o-, m-, and p-nitrooxymethylbenzoate derivatives (3-5), respectively, furnish stable compounds that release NO and inhibit the GC receptors in biological assays. To improve solubility we introduced a more water-soluble linker such as the nitrooxyalkylpiperidine or -piperazine group (6-9). Also these compounds retained properties of both NO and prednisolone. Compound 5 (NCX 1015) was selected for its better profile: enhanced antiinflammatory properties and reduced side effects compared with prednisolone. NCX 1015 is currently under preclinical development.

It was demonstrated in the early 1990s that adenosine exerts many physiological functions through the interaction with four different receptors, named A1, A2A, A2B, and A3. In the past few years, our group has been involved in the development of A2A antagonists, which led to the synthesis of SCH 58261 (1), the first potent and selective adenosine A2A antagonist, which has been widely used as a reference compound. In this paper, we present an extended series of pyrazolotriazolopyrimidines synthesized with the aim to investigate the influence of the substitutions on the pyrazole ring. The choice of the substituents was based on their capability to improve water solubility while retaining high affinity and selectivity at the human A2A adenosine receptor subtype. In this series, some structural characteristics that are important for activity, i.e., tricyclic structure, free amino group at 5-position, furan ring, and substituent at 7-position on the pyrazole moiety, have been maintained. We focused our attention on the nature of the phenyl ring substituent to improve water solubility. Following this strategy, we developed new compounds with good affinity and selectivity for A2A adenosine receptors, such as 8d (K(i) 0.12 nM; hA1/hA2A ratio = 1025; R(m) = 2.8), 8h (K(i) 0.22; hA1/hA2A ratio = 9818; R(m) = 3.4), 8i (K(i) 0.18 nM; hA1/hA2A ratio = 994; R(m) = 2.8), 8k (K(i) 0.13 nM; hA1/hA2A ratio = 4430; R(m) = 3.6), and 14b (K(i) 0.19 nM; hA1/hA2A ratio = 2273; R(m) = 2.7). All the new synthesized compounds have no significant interaction with either A2B or A3 receptor subtypes. This new series of compounds deeply enlightens some structural requirements to display high affinity and selectivity for the A2A adenosine receptor subtype, although our goal of identifying new compounds with increased water solubility was not completely achieved. On this basis, other strategies will be devised to improve this class of compounds with a profile that appears to be promising for treatment of neurodegenerative disorders, such as Parkinson's disease.