Synthesis of Nitro Esters of Prednisolone, New Compounds Combining Pharmacological Properties of Both Glucocorticoids and Nitric Oxide

Abstract

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.

The Distinct Alterations Produced in Cardiovascular Functions by Prednisolone and Nitro-prednisolone (NCX-1015) in the Rat Highlight a Causal Role for Endothelin-1

“…at ASPET Journals on May 11, 2018 jpet.aspetjournals.org nitrate species (Baraldi et al, 2004). Relevantly, the impact of NO species released from NCX-1015 becomes of particular relevance after longer in vitro incubations or prolonged treatment as in the present study.…”

“…Supported by these reasons, the present study was designed to compare the effects of prolonged treatment with a widely used GC such as prednisolone in relation to its NO-releasing nitro-steroid, or NCX-1015. NCX-1015 is emerging as a prototype of a new class of GC able to release NO species in biological fluids [see Baraldi et al, (2004) for electron spin resonance analyses] thus endowed with anti-inflammatory actions (Paul-Clark et al, 2000;Perretti et al, 2003). In our hands, prednisolone administration to rats produced marked alterations in the cardiovascular system that followed both a time-and dosedependent profile.…”

Therapeutic Potential of Nitrate Esters of Commonly Used Drugs

“…Several prednisolone derivatives have been synthesized with the aim of increasing both solubility and potency. Among them, NCX 1015 has been confirmed to be more potent than prednisolone [77].…”

The nitrosterols – a step forward from the steroid anti-inflammatory drugs?

“…This intermediate was then treated with silver nitrite, acetonitrile and tetrahydrofuran in the dark for 35 h to yield NCX-1015 [11]. The synthesis of NCX-1015 and related compounds has recently been described in detail [12]. Although the substitution of the phenyl group of NCX-1015 with piperidine or piperazine rings increased solubility, NCX-1015 was more effective than the more soluble agents at inhibiting white-cell recruitment in the zymosan-injection model of acute inflammation [12].…”

“…NCX-1015 1 µM displaces 47% of the binding of [ 3 H]dexamethasone to the glucocorticoid receptors of human peripheral blood mononuclear cells (PBMCs) [12]. In the initial study of NCX-1015, two markers of glucocorticoid activity were used; IL-1β production from lipopolysaccharide (LPS)-stimulated PBMCs, and the expression of the human mononuclear phagocyte-specific antigen, CD163 [11].…”