Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase
Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase
复制标题
DOI：
10.1021/jm401603e
复制
发表时间：
2014-03-27
影响因子：
7.3
通讯作者：
Pugovics, Osvalds
中科院分区：
文献类型：
--
作者：
Tars, Kaspars;Leitans, Janis;Pugovics, Osvalds
γ-丁基甜菜碱羟化酶（BBOX）催化γ-丁基甜菜碱（GBB）转化为L-肉毒碱，其参与从长链脂肪酸产生代谢能量。BBOX抑制剂3-（1，1，1-三甲基肼-1-鎓-2-基）丙酸盐（米屈肼）是一种批准的临床使用的心脏保护药物，是一种相对较差的BBOX抑制剂，需要高的日剂量。在本文中，我们描述了51个化合物的设计，合成和性质，其中包括GBB和米屈肼类似物。我们已经发现了具有改善的IC 50值的新型BBOX抑制剂;最好的例子是在纳摩尔范围内，与米屈肼相比约好2个数量级。对六种缓蚀剂与BBOX配合物的晶体结构进行了解析，解释了它们的活性，为进一步的缓蚀剂设计奠定了基础。
gamma-Butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to L-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids. BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate (mildronate), which is an approved, clinically used cardioprotective drug, is a relatively poor BBOX inhibitor and requires high daily doses. In this paper we describe the design, synthesis, and properties of 51 compounds, which include both GBB and mildronate analogues. We have discovered novel BBOX inhibitors with improved IC50 values; the best examples are in the nanomolar range and about 2 orders of magnitude better when compared to mildronate. For six inhibitors, crystal structures in complex with BBOX have been solved to explain their activities and pave the way for further inhibitor design.