Synthesis and Biological Evaluation of 2-Phenylpyran-4-ones:  A New Class of Orally Active Cyclooxygenase-2 Inhibitors

Abstract

A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.

The Janus Face of Cyclooxygenase-2 in Ischemic Stroke

“…Therefore, inhibition of the COX-2 pathway with most of the drugs available today does not seem a viable option for stroke treatment. COX-2 inhibitors with a safer cardiovascular profile, such as lumiracoxib, and third-generation inhibitors 41 might prove to be more suitable. In addition, new therapeutic strategies targeting the factors mediating the damage downstream of COX-2 offer great promise.…”

Synthesis of 4‐(4‐Methylsulfonylphenyl)‐3‐phenyl‐2(3H)‐thiazole Thione Derivatives as New Potential COX‐2 Inhibitors

“…10,11 The commercially available starting material thioanisole 6 was subjected to Friedel-Craft reaction with acetic anhydride 12 and then oxidation by MCPBA to yield 4-methylsulfonyl-acetophenone (8), 13,14 which was treated with Br 2 in CHCl 3 to afford phenacyl bromide derivative 9. On the other hand, condensation of aniline derivatives 10 with carbon disulfide in the presence of triethylamine gave the corresponding dithiocarbamate salt 11.…”

“…The characterization of the target compounds 5a-5h was based on the 1 H NMR, 13 C NMR, infrared and mass spectral data. In the 1 H NMR spectrum, the CH 2 signal at δ 4.46 disappeared when compound 9 was converted to compounds 5, instead a new signal of δ 6.72-6.78 originated from H-5 of thiazole thione was observed.…”

“…The IR spectra were obtained on a Shimadzu 470 spectrophotometer with potassium bromide disks. NMR spectra were measured using solvent of CDCl 3 on a Bruker 80 or 500 spectrometer with 1 H NMR at 80 MHz or 13 A mixture of aniline derivatives 10 (1.5 mmol), carbon disulfide (1.8 mmol), and triethylamine (4.5 mmol) was stirred at room temperature overnight. The precipitated crystals were collected and washed with ether to yield 11 as a slightly pale yellow or yellow crystals.…”

Synthesis of N-[2-(2,4-Difluorophenoxy)trifluoromethyl-3-pyridyl]sulfonamides and Their Inhibitory Activities against Secretory Phospholipase A2

“…In fact, many successful cases for enhancing an activity have been reported with this substituent. [12][13][14][15][16][17] In this paper, we report the synthesis of these derivatives 3-6 and describe their inhibitory activities against sPLA 2 .…”