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Prevention and rescue of cardiac dysfunction by methanocarba adenosine monophosphonate derivatives.
Purinergic Signalling ( IF 3.0 ) Pub Date : 2020-01-27 , DOI: 10.1007/s11302-020-09688-0
Jian-Bing Shen 1 , Kiran S Toti 2 , Saibal Chakraborty 2 , T Santhosh Kumar 2 , Chunxia Cronin 1 , Bruce T Liang 1 , Kenneth A Jacobson 2
Affiliation  

Accumulating evidence supports a therapeutic role of purinergic signaling in cardiac diseases. Previously, efficacy of systemically infused MRS2339, a charged methanocarba derivative of 2-Cl-adenosine monophosphate, was demonstrated in animal models of heart failure. We now test the hypothesis that an uncharged adenine nucleoside phosphonate, suitable as an oral agent with a hydrolysis-resistant phospho moiety, can prevent the development of cardiac dysfunction in a post-infarction ischemic or pressure overload-induced heart failure model in mice. The diester-masked uncharged phosphonate MRS2978 was efficacious in preventing cardiac dysfunction with improved left ventricular (LV) fractional shortening when administered orally at the onset of ischemic or pressure overload-induced heart failure. MRS2925, the charged, unmasked MRS2978 analog, prevented heart dysfunction when infused subcutaneously but not by oral gavage. When administered orally or systemically, MRS2978 but not MRS2925 could also rescue established cardiac dysfunction in both ischemic and pressure overload heart failure models. The diester-masked phosphate MRS4074 was highly efficacious at preventing the development of dysfunction as well as in rescuing pressure overload-induced and ischemic heart failure. MRS2978 was orally bioavailable (57–75%) giving rise to MRS2925 as a minor metabolite in vivo, tested in rats. The data are consistent with a novel therapeutic role of adenine nucleoside phosphonates in systolic heart failure.

中文翻译:

甲氨基甲酸腺苷单膦酸酯衍生物预防和挽救心脏功能障碍。

越来越多的证据支持嘌呤能信号传导在心脏病中的治疗作用。以前,在心力衰竭的动物模型中证实了全身性输注MRS2339(一种带电荷的2-Cl-腺苷单磷酸的甲氨基甲酸酯衍生物)的功效。现在,我们测试以下假设:不带电荷的腺嘌呤核苷膦酸酯适合用作具有抗水解磷酸部分的口服药物,可以预防小鼠在梗死后局部缺血或压力超负荷引起的心力衰竭模型中心脏功能障碍的发展。当在局部缺血或压力超负荷引起的心力衰竭发作时口服给予二酯掩蔽的不带电荷的膦酸酯MRS2978可以有效地预防心脏功能障碍,改善左心室(LV)分数缩短。MRS2925(已充电,未屏蔽的MRS2978类似物)皮下注射可预防心脏功能障碍,但不能通过管饲法预防。当口服或全身给药时,MRS2978而非MRS2925还可在缺血性和压力超负荷心力衰竭模型中挽救既定的心脏功能障碍。二酯掩蔽的磷酸酯MRS4074在预防功能障碍的发展以及挽救压力超负荷引起的缺血性心力衰竭方面非常有效。在大鼠中测试,MRS2978具有口服生物利用度(57–75%),成为体内的次要代谢产物MRS2925。该数据与腺嘌呤核苷膦酸酯在收缩性心力衰竭中的新型治疗作用一致。在缺血性和压力超负荷心力衰竭模型中,MRS2978而非MRS2925还可挽救已确立的心脏功能障碍。二酯掩蔽的磷酸酯MRS4074在预防功能障碍的发展以及挽救压力超负荷引起的缺血性心力衰竭方面非常有效。在大鼠中测试,MRS2978具有口服生物利用度(57–75%),成为体内的次要代谢产物MRS2925。该数据与腺嘌呤核苷膦酸酯在收缩性心力衰竭中的新型治疗作用一致。在缺血性和压力超负荷心力衰竭模型中,MRS2978而非MRS2925还可挽救已确立的心脏功能障碍。二酯掩蔽的磷酸酯MRS4074在预防功能障碍的发展以及挽救压力超负荷引起的缺血性心力衰竭方面非常有效。在大鼠中测试,MRS2978具有口服生物利用度(57–75%),成为体内的次要代谢产物MRS2925。数据与腺嘌呤核苷膦酸酯在收缩性心力衰竭中的新型治疗作用一致。在大鼠中测试,MRS2978具有口服生物利用度(57-75%),成为体内的次要代谢产物MRS2925。该数据与腺嘌呤核苷膦酸酯在收缩性心力衰竭中的新型治疗作用一致。在大鼠中测试,MRS2978具有口服生物利用度(57–75%),成为体内的次要代谢产物MRS2925。该数据与腺嘌呤核苷膦酸酯在收缩性心力衰竭中的新型治疗作用一致。
更新日期:2020-01-27
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