Synthesis, structure-property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y12 receptor
Synthesis, structure-property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y12 receptor
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DOI：
10.1016/j.ejmech.2013.04.007
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发表时间：
2013-07-01
影响因子：
6.7
通讯作者：
Zetterberg, Fredrik
中科院分区：
文献类型：
--
作者：
Bach, Peter;Bostrom, Jonas;Zetterberg, Fredrik
本文描述了一系列新的P2 Y（12）受体拮抗剂的开发，其基于我们先前报道的哌嗪基脲系列1（IC_（50）结合亲和力= 0.33 μ M，水溶解度= 300 μ M/min/mg）。通过用磺酰脲基团取代脲官能团，我们观察到亲和力沿着增加，同时稳定性和溶解性也得到改善，如47所示（IC 50结合亲和力= 0.042 μ M，水溶性= 90 μ M，微粒体克林特（HLM）= 70 μ M/min/mg）。通过用3-氨基氮杂环丁烷取代中心哌嗪环，实现了亲和力和代谢稳定性的进一步改善，如3所示（IC 50结合亲和力= 0.0062 μ M，水溶性= 83 μ M，微粒体克林特（HLM）= 28 μ M/min/mg）。在体外结合试验中观察到的亲和力改善也转化为在WPA聚集试验中观察到的效力（47：19 nM和3：9.5 nM），并且观察到的体外ADME特性转化为在大鼠中观察到的体内PK特性。此外，我们发现，磺酰脲类化合物在溶液中长期储存期间的化学稳定性与磺酰脲连接体有关，并取决于溶剂的类型和磺酰脲官能团的取代模式。(C)2013年Elsevier Masson SAS。All rights reserved.
The present paper describes the development of a new series of P2Y(12) receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 mu M, aq solubility = 300 mu M/min/mg). By replacement of the urea functionality with a sulfonylurea group we observed increased affinity along with improved stability and solubility as exemplified by 47 (IC50 binding affinity = 0.042 mu M, aq solubility = 90 mu M, microsomal CLint (HLM) = 70 mu M/min/mg). Further improvements in affinity and metabolic stability were achieved by replacing the central piperazine ring with a 3-aminoazetidine as exemplified by 3 (IC50 binding affinity = 0.0062 mu M, aq solubility = 83 mu M, microsomal CLint (HLM) = 28 mu M/min/mg). The improved affinity observed in the in vitro binding assay also translated to the potency observed in the WPA aggregation assay (47: 19 nM and 3: 9.5 nM) and the observed in vitro ADME properties translates to the in vivo PK properties observed in rat. In addition, we found that the chemical stability of the sulfonylureas during prolonged storage in solution was related to the sulfonyl urea linker and depended on the type of solvent and the substitution pattern of the sulfonyl urea functionality. (C) 2013 Elsevier Masson SAS. All rights reserved.