PubMed · 9345848
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R Botting, J Vane. 1997. Re-addressing relative selectivities.. https://doi.org/10.1016/s0165-6147(97)90654-4
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A new group of 3-(4-substituted-phenyl)-4-(4-methylsulfonamidophenyl)-2(5H)furanones in which the methylsulfonyl (MeSO(2)) COX-2 pharmacophore present in rofecoxib was replaced by a methanesulfonamido (MeSO(2)NH) moiety, and where the substituent at the para-position of the C-3 phenyl ring was simultaneously varied (H, F, Cl, Br, Me, OMe), were evaluated to determine the combined effects of steric and electronic substituent properties upon COX-1 and COX-2 inhibitory potency and COX isozyme selectivity. Structure-activity relationship (SAR) studies showed that compounds having a neutral (H), or electronegative halogen (F, Cl, Br), substituent at the para-position of the C-3 phenyl ring inhibited both COX-1 and COX-2 with COX-2 selectivity indexes in the 3.1-39.4 range. In contrast, compounds having an electron-donating Me or OMe substituent were selective inhibitors of COX-2 (COX-1 IC(50)>100 microM). These SAR data indicate the 3-aryl-4-(4-methylsulfonamidophenyl)-2(5H)furanone scaffold provides a suitable template to design COX inhibitors with variable COX-2 selectivity indexes.
Programmed proliferative degeneration of the human fetal ductus arteriosus (DA) in preparation for its definite postnatal closure has a large developmental variability and is controlled by several signaling pathways, most prominently by prostaglandin (PG) metabolism. Numerous studies in various mammalian species have shown interspecies and developmental differences in ductal protein expression of cyclooxygenase (COX) isoforms and PG E receptor subtypes (EP1-4). We examined COX1, COX2, and EP4 receptor protein expression immunohistochemically in 57 human fetal autopsy DA specimens of 11-38 wk of gestation. According to their histologic maturity, specimens were classified into four stages using a newly designed maturity score that showed that histologic maturity of the DA was not closely related to gestational age. COX1 expression was found in all DA regions and rose steadily during development. COX2 staining remained weak throughout gestation. EP4 receptor staining increased moderately during gestation and was limited to the intima and media. In conclusion, histologic maturity classification helps to address developmentally regulated processes in the fetal DA. Concerning prostaglandin metabolism our findings are in line with animal studies, which assigned COX1 the predominant role in the DA throughout gestation. EP4 receptor presumably plays a key role for active patency of the human DA in the third trimester.
Radiation therapy is one of the three major treatment modalities used in eradicating malignant tumours. When ionising radiation is used to treat abdominal tumours, severe side effects largely due to mucosal damage in the alimentary tract are common, particularly when it is combined with chemotherapy. Radiation-induced mucositis may not only limit the therapeutic doses of combined treatment but also adversely affect the quality of life of the patient. Treatment strategies to treat and prevent radiation-induced mucositis have been reviewed and published in the Clinical Practice Guidelines, 2004. However evidence supporting an effective treatment approach is tenuous, probably because the mechanistic evolution of radiation-induced mucositis is poorly understood. Several animal models have been used to examine the various effects of radiation but no single animal model has been able to effectively capture the effects of radiation on the alimentary tract at the molecular level before symptoms begin. This review will outline the events which occur following radiation exposure; from chromosomal aberrations in the mucosal cells leading to apoptotic and mitotic death, to the evolution of mucositis involving changes in gene activations and signaling. A better understanding of the mechanisms of radiation therapy-induced mucositis is necessary as it will allow for future pharmaceutical interventions to alleviate if not eliminate the debilitating side effects.