title: Enhancing the pharmacodynamic profile of a class of selective COX-2 inhibiting nitric oxide donors.
abstract: We report herein the development, synthesis, physicochemical and pharmacological characterization of a novel class of pharmacodynamic hybrids that selectively inhibit cyclooxygenase-2 (COX-2) isoform and present suitable nitric oxide releasing properties. The replacement of the ester moiety with the amide group gave access to in vivo more stable and active derivatives that highlighted outstanding pharmacological properties. In particular, the glycine derivative proved to be extremely active in suppressing hyperalgesia and edema.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185 Roma, Italy. Electronic address: mariangela.biava@uniroma1.it.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Battilocchio
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Poce
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Alfonso
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Consalvi
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Di Capua
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Alma
authors.initials: A
authors.lastname: Martelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Dipartimento di Neurologia, Psicologia, Area del Farmaco e Salute del Bambino, Università degli Studi di Firenze, Viale G. Pieraccini 6, I-50139 Firenze, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Dipartimento di Neurologia, Psicologia, Area del Farmaco e Salute del Bambino, Università degli Studi di Firenze, Viale G. Pieraccini 6, I-50139 Firenze, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Rottapharm Madaus, Via Valosa di Sopra 7, 20052 Monza, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordani
authors.affiliation: Rottapharm Madaus, Via Valosa di Sopra 7, 20052 Monza, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Persiani
authors.affiliation: Rottapharm Madaus, Via Valosa di Sopra 7, 20052 Monza, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Colovic
authors.affiliation: Neuroscienze e Imaging, Università "G. d'Annunzio" di Chieti and CeSI, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Dovizio
authors.affiliation: Neuroscienze e Imaging, Università "G. d'Annunzio" di Chieti and CeSI, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Patrignani
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
mesh_terms: D019342:Acetic Acid; D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002351:Carrageenan; D002460:Cell Line; D003251:Constriction, Pathologic / Q000139:chemically induced / Q000188:drug therapy; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry*; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D052246:Cyclooxygenase 2 Inhibitors; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D002351:Carrageenan; D051546:Cyclooxygenase 2; D019342:Acetic Acid; D005998:Glycine
keywords: (t)NSAIDs; 1,5-Diarylpyrroles; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; 1-hydroxybenzotriazole; 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; AA; Boc; CBz; CINODs; COX-2; CV; Coxibs; Cyclooxygenases; DMAP; DMEM; Dulbecco’s modified eagle’s medium; E(max); EDCI; FBS; GI; HOBt; HWB; LPS; NO; NO releasing moiety (nitroxy)butanol; NOBA; NSAIDs; Nitric oxide; OA; ODQ; PBS; PGE(2); Pharmacodynamic hybrids; PyBOP; RA; RIA; SAR; SGF; TX; arachidonic acid; benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; cNOS; carboxybenzyl; cardiovascular; constitutive nitric oxide synthases; coxibs; cyclooxygenase 2; cyclooxygenase-2 inhibitors; cyclooxygenase-inhibiting nitric oxide donor; dimethylaminopyridine; fetal bovine serum; gastrointestinal; human whole blood; intraperitoneal; intraplantar; ip; ipl; lipopolysaccharide; maximal vasorelaxing response; nitric oxide; nonsteroidal anti-inflammatory drug; osteoarthritis; phosphate buffer solution; prostaglandin E(2); radioimmunoassay; rheumatoid arthritis; simulated gastric fluid; structure relationship studies; tert-butyloxycarbonyl; thromboxane; traditional nonsteroidal anti-inflammatory drug