title: Diarylheterocycle core ring features effect in selective COX-1 inhibition.
abstract: The COX-1 isoenzyme plays a significant role in a variety of diseases, as it catalyzes the bioprocesses behind many health problems. Among the diarylheterocycle class of COX inhibitors, the isoxazole ring has been widely used as a central heterocycle for the preparation of potent and selective COX-1 inhibitors such as P6 [3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole]. The role of the isoxazole nucleus in COX-1 inhibitor selectivity has been clarified by preparing a set of new diarylheterocycles with various heterocycle cores. Replacement of isoxazole with isothiazole or pyrazole gave a drastic decrease in COX-1 inhibitory activity, whereas the introduction of an electron-donating group (EDG) on the N-aryl pyrazole allowed recovery of COX-1 inhibitory activity and selectivity. The EDG-equipped 5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (17) selectively inhibits COX-1 activity (IC(50) =3.4 μM; 28% COX-2 inhibition at 50 μM), in contrast to its inactive analogue, 3-(furan-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole, which does not bear the methoxy EDG. Molecular docking studies of compound 17 into the binding site of COX-1 shed light on its binding mode.
authors.affiliation: Dipartimento Farmaco-Chimico, Università degli Studi di Bari A. Moro via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Perrone
authors.forename: Paola
authors.initials: P
authors.lastname: Vitale
authors.forename: Paola
authors.initials: P
authors.lastname: Malerba
authors.forename: Angela
authors.initials: A
authors.lastname: Altomare
authors.forename: Rosanna
authors.initials: R
authors.lastname: Rizzi
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Carmen
authors.initials: C
authors.lastname: Di Giovanni
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Antonio
authors.initials: A
authors.lastname: Scilimati
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2