Retooling Manganese(III) Porphyrin-Based Peroxynitrite Decomposition Catalysts for Selectivity and Oral Activity: A Potential New Strategy for Treating Chronic Pain

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• 作者：Smita Rausaria ; Mahsa M. E. Ghaffari ; Andrew Kamadulski ; Kenny Rodgers ; Leesa Bryant ; Zhoumou Chen ; Tim Doyle ; Michael J. Shaw ; Daniela Salvemini ; William L. Neumann
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8658-8669
• 全文大小：571K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

Redox-active metalloporphyrins represent the most well-characterized class of catalysts capable of attenuating oxidative stress in vivo through the direct interception and decomposition of superoxide and peroxynitrite. While many interesting pharmacological probes have emerged from these studies, few catalysts have been developed with pharmaceutical properties in mind. Herein, we describe our efforts to identify new Mn(III)鈥損orphyrin systems with enhanced membrane solubilizing properties. To this end, seven new Mn(III)-tetracyclohexenylporphyin (TCHP) analogues, 7, 10, 12, 15, and 16a鈥?b>c, have been prepared in which the beta-fused cyclohexenyl rings provide a means to shield the charged metal center from the membrane during passive transport. Compounds 7, 15, and 16a鈥?b>c have been shown to be orally active and potent analgesics in a model of carrageenan-induced thermal hyperalgesia. In addition, oral administration of compound 7 (10鈥?00 mg/kg, n = 5) has been shown to dose dependently reverse mechano-allodynia in the CCI model of chronic neuropathic pain.