Structural requirements of bile acid transporters: C-3 and C-7 modifications of steroidal hydroxyl groups.
Structural requirements of bile acid transporters: C-3 and C-7 modifications of steroidal hydroxyl groups.
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DOI：
10.1016/j.ejps.2012.02.012
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发表时间：
2012-05-12
影响因子：
4.6
通讯作者：
Polli, James E.
中科院分区：
文献类型：
--
作者：
Kolhatkar, Vidula;Polli, James E.
顶端钠依赖性胆汁酸转运蛋白（ASBT）和牛磺胆酸钠共转运多肽（NTCP）是潜在的前药靶标，但这些转运蛋白的结构要求尚未完全确定。本研究的目的是评估 C-3 和 C-7 取代对胆汁酸与这些胆汁酸转运蛋白相互作用的影响。针对 ASBT 和 NTCP 测试了 19 种胆汁酸类似物的结合和易位。结果表明，ASBT 和 NTCP 容纳了多种用于结合的取代基，但所有主要的 C-7 修饰都导致类似物未表现出被 ASBT 或 NTCP 主动摄取。 C-7 不耐受的 C-3 修饰仍然通过 ASBT 和 NTCP 提供易位，证实了 C-7 修饰的相对不可接受性。 ASBT 和 NTCP 都表现出大致相似的结合效力。结果表明，药物与 C-3 羟基而不是 C-7 羟基的缀合有可能成功产生靶向 ASBT 和 NTCP 的前药。
The apical sodium dependent bile acid transporter (ASBT) and sodium-taurocholate cotransporting polypeptide (NTCP) are potential prodrug targets, but the structural requirements for these transporters are incompletely defined. The objective of this study was to evaluate the effect of C-3 and C-7 substitution on bile acid interaction with these bile acid transporters. Nineteen bile acid analogues were tested against ASBT and NTCP for binding, as well as translocation. Results indicated that ASBT and NTCP accommodated a wide range of substituents for binding, but all major C-7 modifications resulted in analogues that did not demonstrate active uptake by either ASBT or NTCP. A C-3 modification that was not tolerated at C-7 still afforded translocation via ASBT and NTCP, confirming the relative unacceptability of C-7 modification. Both ASBT and NTCP demonstrated a generally similar binding potency. Results suggest that drug conjugation to the C-3 hydroxyl group, rather than C-7, has potential to lead to a successful prodrug targeting ASBT and NTCP.
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DOI：
10.1124/jpet.107.135863
发表时间：
2008-07-01
影响因子：
3.5
作者：
Gonzalez, Pablo;Polli, James E.
通讯作者：
Polli, James E.
影响因子：
3.7
作者：
Balakrishnan, A;Sussman, DJ;Polli, JE
通讯作者：
Polli, JE
影响因子：
3.9
作者：
Han, Yong-Hae;Busler, Dennis;Rodrigues, A. David
通讯作者：
Rodrigues, A. David
影响因子：
3.7
作者：
Kolhatkar, Vidula;Polli, James E.
通讯作者：
Polli, James E.
影响因子：
7.3
作者：
Rais, Rana;Acharya, Chayan;Polli, James E.
通讯作者：
Polli, James E.