Diarylspiro[2.4]heptenes as Orally Active, Highly Selective Cyclooxygenase-2 Inhibitors:  Synthesis and Structure−Activity Relationships

Abstract

A novel series of 5,6-diarylspiro[2.4]hept-5-enes was shown to provide highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. A study of structure-activity relationships in this series suggests that 3,4-disubstituted phenyl analogs are generally more selective than 4-substituted phenyl analogs and that replacement of the methyl sulfone group on the 6-phenyl ring with a sulfonamide moiety results in compounds with superior in vivo pharmacological properties, although with lower COX-2 selectivity. Several compounds have been shown to possess promising pharmacological properties in adjuvant-induced arthritis and edema analgesia models. The absence of gastrointestinal (GI) toxicity at 200 mpk of several selected compounds in rats and mice corresponds well with the weak potency for inhibition of COX-1 observed in the enzyme assay. Methyl sulfone 55 and sulfonamide 24 were shown to have superior in vivo pharmacological profiles, low GI toxicity, and good oral bioavailability and duration of action.

Pharmacological evaluation of 1-(carboxymethyl)-3,5-diphenyl-2-methylbenzene, a novel arylacetic acid with potential anti-inflammatory properties

“…The pharmacophore found in the structure-activityrelationship of selective COX-2 inhibitors appears to be of the general formula aryl methyl sulfonyl and aryl methyl sulfonamide as opposed to the aryl acetic acid and aryl propionic acid found in the non-selective agents [37,38]. This suggests that the binding interaction of COX-2 might be different in its sensitivity to both the electronic and stearic properties of the substitution on the aryl portion.…”

Comparative residue interaction analysis (CoRIA): a 3D-QSAR approach to explore the binding contributions of active site residues with ligands

“…The test system was a set of COX-2 inhibitors comprising pyrrole [30], imidazole [31,32], cyclopentene [33,34], benzene [35], pyrazole [36], spiroheptene [37], isoxazole [38], pyridine [39], thiazolone [40], thiadiazole and oxadiazole [41] derivatives. The inhibitory activities of all these molecules were measured on human recombinant enzyme by the same protocol, and are reported as IC 50 values [30][31][32][33][34][35][36][37][38][39][40][41].…”

“…The inhibitory activities of all these molecules were measured on human recombinant enzyme by the same protocol, and are reported as IC 50 values [30][31][32][33][34][35][36][37][38][39][40][41]. The enzyme inhibitory activities were converted to the negative logarithmic scale (pIC 50 ) and as seen in Table 1 spans 5 log orders.…”

Structural diversity of selective COX-2 inhibitors

“…Examples of diarylcarbocycles include four-membered (e.g., cyclobutene and cyclobutenone) [48], five-membered (e.g., cyclopentene and cyclopentenone) [49][50][51], spirocyclic [52,53] and substituted phenyl ring (terphenyl) systems [54,55]. Although preliminary SAR studies suggested that the central ring was essential for favorable spatial orientation of the two pendant phenyl rings, a series of 1,2-and l,l-diarylstilbenes were recently disclosed as potent and selective COX-2 inhibitors [56][57][58].…”