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Improving the Solubility of a New Class of Antiinflammatory Pharmacodynamic Hybrids, that Release Nitric Oxide and Inhibit Cycloxygenase-2 Isoenzyme Original Research Article

European Journal of Medicinal Chemistry, In Press, Accepted Manuscript, Available online 18 October 2012

Mariangela Biava, Claudio Battilocchio, Giovanna Poce, Salvatore Alfonso, Sara Consalvi, Giulio Cesare Porretta, Silvia Schenone, Vincenzo Calderone, Alma Martelli, Lara Testai, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Lidia Sautebin, Antonietta Rossi, Antonio Giordani, Paola Patrignani, Maurizio Anzini
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► Pharmacodynamic hybrids inhibiting COX-2 isoenzyme. ► Improved solubility due the introduction of an ionisable moiety on the side chain. ► An enhanced nitric oxide releasing profile was highlighted by ex-vivo studies. ► In vivo testing highlighted anti-nociceptive properties for this compounds.



Abstract
The development of a novel class of pharmacodynamic hybrids that inhibits COX-2 isoform is reported. These molecules display enhanced nitric oxide releasing properties due to the presence of an ionisable moiety. The in vivo analgesic/anti-inflammatory activity was maintained in relation to the parent compounds.
Article Outline

1. Introduction
2. Chemistry
3. Results and discussion
3.1. Solubility assessment in SGF and PBS solutions
3.2. Cell-based cyclooxygenases inhibition assay
3.3. Reduction of acetic acid-induced abdominal constrictions in mice
3.4. Reduction of carrageenan-induced inflammatory condition in rats
3.5. Nitric oxide releasing properties
4. Conclusions
5. Experimental protocols
5.1. Chemistry
Procedure for the synthesis of 1-[4-(methylthio)phenyl]pentane-1,4-dione (4)
Procedure for the synthesis of 1-[4-(methylsulfonyl)phenyl]pentane-1,4-dione (5)
General procedure for the preparation of 1,5-diarylpyrroles (6a-b)
General procedure for the preparation of ethyl (1,5diaryl-pyrrol)glyoxylate (7a-b)
General procedure for the preparation of ethyl-2-(hydroxyimino)-(1,5-diarylpyrrol) acetate (8a-b)
Ethyl 2-(hydroxyimino)-2-[2-methyl-5-[4-(methylsulfonyl)phenyl]-1-(4-fluorophenyl)-1H-pyrrol-3-yl]acetate (8a)
Ethyl 2-(hydroxyimino)-2-[2-methyl-5-[4-(methylsulfonyl)phenyl]-1-(3-fluorophenyl)-1H-pyrrol-3-yl]acetate (8b)
General procedure for the preparation of ethyl 2-amino-(1,5-diarylpyrrol)acetate (9a-b)
Ethyl 2-amino-2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate (9a)
Ethyl 2-amino-2-[1-(3-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate (9b)
General procedure for the preparation of tert-butyl (ethoxycarbonyl)(1,5-diarylpyrrol)carbamate (10a-b)
tert-Butyl (ethoxycarbonyl)-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]methyl carbamate (10a)
1H-pyrrol-3-yl]methyl carbamate (10b)
Procedure for the Preparation of benzyl (ethoxycarbonyl)(1,5-diarylpyrrol)carbamate (13a-b)
N-Benzyl-(ethoxycarbonyl)-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]methylcarbamate (13a)
tert-Butyl (ethoxycarbonyl)-[1-(3-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-N-Benzyl-(ethoxycarbonyl)-[1-(3-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]methylcarbamate (13b)
Procedure for the preparation of protected (Boc and Cbz) (1,5-diarylpyrrol)glycine (11a-b, 14a-b)
N-tert-Butyl-2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]-2-amino-acetic acid (11a)
N-tert-Butyl-2-[1-(3-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]-2-amino-acetic acid (11b)
N-(Benzyloxy)carbonyl-2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]-2-amino-acetic acid (14a)
N-(Benzyloxy)carbonyl-2-[1-(3-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]-2-amino-acetic acid (14b)
General procedure for the preparation of protected (Cbz and Boc) α-(1,5-Diarylpyrrole)-glycine nitroxyalkyl esters (12a−d, 15a−d)
3-(Nitroxy)propyl N-tert-butyl-(ethoxycarbonyl)-2-(1-(4-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-3-yl)-2-amino-acetate (12a)
3-(Nitroxy)propyl] N-tert-butyl-(ethoxycarbonyl)-2-(1-(3-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-3-yl)-2-amino-acetate (12b)
4-(Nitroxy)butyl N-tert-butyl-(ethoxycarbonyl)-2-(1-(4-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-3-yl)-2-amino-acetate (12c)
4-(Nitroxy)butyl N-tert-butyl-(ethoxycarbonyl)-2-[1-(3-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]-2-amino-acetate (12d)
3-(Nitroxy)propyl N-benzyl-(ethoxycarbonyl)-2-(1-(4-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-3-yl)-2-amino-acetate (15a)
3-(Nitroxy)propyl N-benzyl-(ethoxycarbonyl)-2-(1-(3-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-3-yl)-2-amino acetate (15b)
4-(Nitroxy)butyl N-benzyl-(ethoxycarbonyl)-2-(1-(4-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-3-yl)-2-amino acetate (15c)
4-(Nitroxy)butyl N-benzyl-(ethoxycarbonyl)-2-(1-(3-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-3-yl)-2-amino acetate (15d)
General procedure for the preparation of α-(1,5-diarylpyrrole)-glycine hydroxyalkyl esters (2a−d)
3-Hydroxypropyl 2-amino-2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate (2a)
3-Hydroxypropyl 2-amino-2-[1-(3-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate (2b)
4-Hydroxybutyl 2-amino-2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate (2c)
3-Hydroxybutyl 2-amino-2-[1-(3-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate (2d)
General procedure for the preparation of α-(1,5-diarylpyrrole)-glycine nitroxyalkyl esters (1a−d)
3-(Nitroxy)propyl 2-amino-2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate (1a)
3-(Nitroxy)propyl 2-amino-2-[1-(3-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate (1b)
4-(Nitroxy)butyl 2-amino-2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate (1c)
4-(Nitroxy)butyl 2-amino-2-[1-(3-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetate (1d)
General procedure for the preparation of hydroxylalkyl nitrates (17a-b)
5.2. Bio-pharmacological testing
Pharmacology
Ex Vivo Vasorelaxing Activity
Determination of the formation of nitrites and nitrates, in rat liver homogenate
In Vivo Analgesic and Anti-Inflammatory Study
5.3. Solubility Assessment in Phosphate Buffered Saline (PBS) and Simulated Gastric Fluid (SGF)