선택적인 싸이클로옥시게나제-1 저해제로서 셀레칵시브의 살리실산 유사체 합성과 약리 효과 연구
초록/요약
Base on the reports that AAD 2004 has potent antioxidant effect and Celecoxib has potent anti-inflammatory effect, we designed a series of salicylic acid analogues of Celecoxib as a new neuroprotective agents. Three main functional groups in the celecoxib’s structure were modified. First, 5-aminosalicylic acid moiety was introduced to improve an anti-oxidant activity. Second, trifluoromethyl group in the 5-membered ring was substituted with other groups. Third, methylphenyl group was replaced with the phenyl group containing different substituent. The anti-oxidant effect by measuring the inhibitory activity against DPPH neurotoxicity showed that compounds 15b and 15d have lower inhibitory activity than AAD 2004. The anti-inflammatory effect by measuring in vitro COX enzyme inhibition revealed that the salicylic acid analogs of Celecoxib showed highly potent and selective COX-1inhibiton rather than COX-2 inhibition. Among the tested compounds, 2-hydroxy-5-[5-(4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-benzoic acid is the most potent compound which have a COX-1 inhibition (IC50 = 3.0 nM) with a high COX-1 selectivity (SI=2651). In addition, the 5-aminosalicylic acid analogues (15a, 15b, 15c, 15d and 15e) showed more potent COX inhibition than the 4-aminosalicylic acid analogs. These results suggested that, unlike the diaryl heterocycle class of COX-2 inhibitors including celecoxib, our celecoxib’s analogs can be developed as a new class of COX-1 inhibitor.
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Ⅰ Introduction
1. Alzheimer’s disease (AD) pathgenesis
Amyloidgenesis
2. Mechanism of Aβ toxicity
1) Contribution of ROS
2) Contribution of constitutive NO
3) Activation of inflammatory mediators
3. Antioxidant neuroprotection in Alzheimer’s disease
4. Inflammation in Alzheimer's disease
1) Role of cyclo-oxygenases
2) Effects of anti-inflammatory agents in human brain
5. The role of cyclo-oxygenases in ovarian cancer
Ⅱ Drug Design
Ⅲ Results and Discussion
Ⅳ Experimental Section
Ⅴ Conclusion
Ⅵ References
Appendix
Abstract
Acknowledgement (in Korean)
