Structure–Activity Relationships Among the Nitrogen Containing Bisphosphonates in Clinical Use and Other Analogues: Time-Dependent Inhibition of Human Farnesyl Pyrophosphate Synthase

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• 作者：James E. Dunford ; Aaron A. Kwaasi ; Michael J. Rogers ; Bobby L. Barnett ; Frank H. Ebetino ; R. Graham G. Russell ; Udo Oppermann ; Kathryn L. Kavanagh
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 10, 2008
• 年：2008
• 卷：51
• 期：7
• 页码：2187 - 2195
• 全文大小：576K
• 年卷期：v.51,no.7(April 10, 2008)
• ISSN：1520-4804

文摘

The nitrogen-containing bisphosphonates (N-BPs) are the main drugs currently used to treat diseases characterized by excessive bone resorption. The major molecular target of N-BPs is farnesylpyrophosphate synthase. N-BPs inhibit the enzyme by a mechanism that involves time dependent isomerization of the enzyme. We investigated features of N-BPs that confer maximal slow and tight-binding by quantifying the initial and final K_is and calculating the isomerization constant K_isom for many N-BPs. Disruption of the phosphonate−carbon−phosphonate backbone resulted in loss of potency and reduced K_isom. The lack of a hydroxyl group on the geminal carbon also reduced K_isom. The position of the nitrogen in the side chain was crucial to both K_i and K_isom. A correlation of K_isom and also final K_i with previously published in vivo potency reveals that the isomerization constant (R = −0.77, p < 0.0001) and the final inhibition of FPPS by N-BPs (R = 0.74, p < 0.0001) are closely linked to antiresorptive efficacy.