title: Novel analgesic/anti-inflammatory agents: 1,5-diarylpyrrole nitrooxyalkyl ethers and related compounds as cyclooxygenase-2 inhibiting nitric oxide donors.
abstract: 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.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. De Gasperi 2, I-53100 Siena, Italy. maurizio.anzini@unisi.it
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Angela
authors.initials: A
authors.lastname: Di Capua
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valenti
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.forename: Michele
authors.initials: M
authors.lastname: Rovini
authors.forename: Germano
authors.initials: G
authors.lastname: Giuliani
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
authors.forename: Luisa
authors.initials: L
authors.lastname: Chiasserini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sega
authors.forename: Giovanna
authors.initials: G
authors.lastname: Poce
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.forename: Alma
authors.initials: A
authors.lastname: Martelli
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.forename: Simona
authors.initials: S
authors.lastname: Pace
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.forename: Veronica
authors.initials: V
authors.lastname: Benetti
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordani
authors.forename: Paola
authors.initials: P
authors.lastname: Anzellotti
authors.forename: Melania
authors.initials: M
authors.lastname: Dovizio
authors.forename: Paola
authors.initials: P
authors.lastname: Patrignani
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004987:Ethers / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010003:Osteoarthritis / Q000188:drug therapy; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D004987:Ethers; D020030:Nitric Oxide Donors; D011758:Pyrroles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human