Identification of a nonbasic, nitrile-containing cathepsin K inhibitor (MK-1256) that is efficacious in a monkey model of osteoporosis.
Identification of a nonbasic, nitrile-containing cathepsin K inhibitor (MK-1256) that is efficacious in a monkey model of osteoporosis.
复制标题
鉴定出一种对骨质疏松猴模型有效的非碱性含腈组织蛋白酶 K 抑制剂 (MK-1256)。
DOI：
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发表时间：
2008
影响因子：
7.3
通讯作者：
S. Crane
中科院分区：
文献类型：
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作者：
J. Robichaud;W. Black;M. Thérien;Julie Paquet;R. Oballa;C. Bayly;D. McKay;Qingping Wang;Elise Isabel;S. Léger;Christophe Mellon;D. Kimmel;G. Wesolowski;M. Percival;F. Massé;S. Desmarais;J. Falgueyret;S. Crane
在这里，我们报告的非碱性，有效的，高选择性，含腈的组织蛋白酶K（Cat K）抑制剂，是建立在我们以前确定的环己烷甲酰胺核心结构的鉴定。在我们的初步研究之后，我们已经发现，掺入五元杂环作为P2-P3接头允许引入甲基砜P3-取代基，这在含有六元芳族P2-P3接头的抑制剂中是不耐受的。P3中五元N-甲基吡唑连接体和甲基砜的组合产生亚纳摩尔Cat K抑制剂，其在我们的功能性骨吸收测定中最小程度地偏移（<10倍）。通过引入2，2，2-三氟乙基取代基解决了由于N-甲基吡唑的代谢去甲基化而产生的问题。最终鉴定出31（MK-1256），这是一种有效（Cat K IC 50 = 0.62 nM）和选择性（对Cat B、L、S、C、H、Z和V的选择性>1100倍，对Cat F的选择性为110倍）的组织蛋白酶K抑制剂，在猴骨质疏松症模型中有效。
Herein, we report on the identification of nonbasic, potent, and highly selective, nitrile-containing cathepsin K (Cat K) inhibitors that are built on our previously identified cyclohexanecarboxamide core structure. Subsequent to our initial investigations, we have found that incorporation of five-membered heterocycles as P2-P3 linkers allowed for the introduction of a methyl sulfone P3-substitutent that was not tolerated in inhibitors containing a six-membered aromatic P2-P3 linker. The combination of a five-membered N-methylpyrazole linker and a methyl sulfone in P3 yielded subnanomolar Cat K inhibitors that were minimally shifted (<10-fold) in our functional bone resorption assay. Issues that arose because of metabolic demethylation of the N-methylpyrazole were addressed through introduction of a 2,2,2-trifluoroethyl substituent. This culminated in the identification of 31 (MK-1256), a potent (Cat K IC 50 = 0.62 nM) and selective (>1100-fold selectivity vs Cat B, L, S, C, H, Z, and V, 110-fold vs Cat F) inhibitor of cathepsin K that is efficacious in a monkey model of osteoporosis.