Isomeric methoxy analogs of nimesulide for development of brain cyclooxygense-2 (COX-2)-targeted imaging agents: Synthesis, in vitro COX-2-inhibitory potency, and cellular transport properties

Isomeric iodinated analogs of nimesulide: Synthesis, physicochemical characterization, cyclooxygenase-2 inhibitory activity, and transport across Caco-2 cells

“…16 The N-phthalimide-protected 2-amino 5-nitrophenol derivative 2 was coupled with mono iodo-substituted aryl boronic acid in the presence of Cu(OAc) 2 as the catalyst, pyridine as the base, and pyridine N-oxide as the oxidant, producing diaryl ethers (3e-g) with satisfactory yields. Deprotection by reduction with hydrazine monohydrate resulted in the 4-nitroaniline derivatives (4e-g) with a quantitative yield.…”

“…17,18 In the present study, we estimated lipophilicity using logP 7.4 values (logarithm of the n-octanol/water partition coefficient at pH 7.4) of the three iodinated analogs of nimesulide, determined by a previously described reversed-phase HPLC method. 16 As shown in Table 1, the lipophilicities of iodinated analogs 1e-g were very similar, with logP 7.4 values of 2.11-2.77, thus demonstrating optimal lipophilicities for passive brain penetration. 19 These iodinated analogs 1e-g had significantly higher logP 7.4 values than nimesulide (logP 7.4 = 1.61) or the methoxy analogs 1b-d (logP 7.4 = 1.26-1.65), reflecting the hydrophobic nature of the substituted iodine atom.…”

“…In contrast, the introduction of iodine at the meta or ortho position of the phenoxy ring, as in compounds 1e and 1f, was highly detrimental to COX-2 inhibitory activity (IC 50 > 100 μM); this effect was also observed for the previously reported ortho-and meta-methoxy analogs, 1b and 1c. 16 This great loss of COX-2 inhibition activity is thought to be due to the increased steric bulk of a substituent at the ortho-or meta-position of the phenoxy ring. None of the isomeric iodo derivatives (1e-g) showed effective inhibition of COX-1 (IC 50 > 100 μM).…”

“…Following this study, we wished to explore the effect of introducing an iodine atom as an alternative substituent, because it has radionuclides that are suitable for biological studies and for multiple imaging applications; these include 123 I for SPECT, 124 I for PET, and 125 I for autoradiography. Although there is a possibility that the introduction of a substituent at the ortho-or meta-position would reduce COX-2 inhibition, 16 the electrostatic differences between the methoxy and iodine substituents could modulate this activity independently of their position. Thus, we developed three regioisomeric iodinated analogs of nimesulide.…”

“…14,15 Based on the established selectivity of nimesulide for COX-2 inhibition and its brain penetration, we designed isomeric methoxy-substituted analogs of nimesulide as potential PET tracers for imaging brain COX-2 expression. Our previous report 16 showed that a para-methoxy substituted analog, 1d (Figure 1), had favorable biochemical and physicochemical properties for further development as a 11 C-labeled PET tracer candidate for brain COX-2 studies. Following this study, we wished to explore the effect of introducing an iodine atom as an alternative substituent, because it has radionuclides that are suitable for biological studies and for multiple imaging applications; these include 123 I for SPECT, 124 I for PET, and 125 I for autoradiography.…”