Document Detail

Novel analgesic/anti-inflammatory agents: 1,5-diarylpyrrole nitrooxyalkyl ethers and related compounds as cyclooxygenase-2 inhibiting nitric oxide donors.
MedLine Citation:
PMID:  23534442     Owner:  NLM     Status:  MEDLINE    
A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7-10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a highlighted good anti-inflammatory and antinociceptive activities. Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties. Finally, molecular modeling and (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed.
Maurizio Anzini; Angela Di Capua; Salvatore Valenti; Simone Brogi; Michele Rovini; Germano Giuliani; Andrea Cappelli; Salvatore Vomero; Luisa Chiasserini; Alessandro Sega; Giovanna Poce; Gianluca Giorgi; Vincenzo Calderone; Alma Martelli; Lara Testai; Lidia Sautebin; Antonietta Rossi; Simona Pace; Carla Ghelardini; Lorenzo Di Cesare Mannelli; Veronica Benetti; Antonio Giordani; Paola Anzellotti; Melania Dovizio; Paola Patrignani; Mariangela Biava
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-04-11
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-26     Completed Date:  2013-07-02     Revised Date:  2013-09-18    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3191-206     Citation Subset:  IM    
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. De Gasperi 2, I-53100 Siena, Italy.
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MeSH Terms
Analgesics / pharmacology*
Anti-Inflammatory Agents, Non-Steroidal / chemistry,  pharmacology*
Cyclooxygenase 1 / metabolism
Cyclooxygenase 2 / drug effects
Cyclooxygenase 2 Inhibitors / chemistry,  pharmacology*
Ethers / chemical synthesis,  pharmacology
Inhibitory Concentration 50
Nitric Oxide Donors / pharmacology*
Osteoarthritis / drug therapy
Pyrroles / chemical synthesis,  chemistry,  pharmacology*
Reg. No./Substance:
0/Analgesics; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/Cyclooxygenase 2 Inhibitors; 0/Ethers; 0/Nitric Oxide Donors; 0/Pyrroles; EC 1; EC 2; EC protein, human
Erratum In:
J Med Chem. 2013 Jun 13;56(11):4821

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