Kobayashi Takaaki, Suemasa Akihiro, Igawa Arisa, Ide Soichiro, Fukuda Hayato, Abe Hiroshi, Arisawa Mitsuhiro, Minami Masabumi, Shuto Satoshi
Faculty of Pharmaceutical Sciences, Hokkaido University , Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Faculty of Pharmaceutical Sciences, Hokkaido University , Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan ; Center for Research and Education on Drug Discovery, Hokkaido University , Kita-ku, Sapporo 060-0812, Japan.
ACS Med Chem Lett. 2014 Jun 16;5(8):889-93. doi: 10.1021/ml500134k. eCollection 2014 Aug 14.
On the basis of the three-dimensional diversity-oriented conformational restriction strategy using key chiral cyclopropane units, we previously identified 3 ((2S,3R)-4-amino-3,4-methanobutyric acid) with a chiral trans-cyclopropane structure as a γ-aminobutyric acid (GABA) transporter inhibitor selective for GABA transporter (GAT) subtypes GAT-3 and BGT-1 (betaine/GABA transporter-1). Further conformational restriction of 3 with the rigid bicyclo[3.1.0]hexane backbone led to the successful development of the first highly potent and selective BGT-1 inhibitor 4 (IC50 = 0.59 μM). The bioactive conformation of 3 for BGT-1 was also identified.
基于使用关键手性环丙烷单元的三维多样性导向构象限制策略，我们之前鉴定出具有手性反式环丙烷结构的3（（2S，3R）-4-氨基-3，4-亚甲基丁酸）作为对γ-氨基丁酸（GABA）转运体亚型GAT-3和BGT-1（甜菜碱/GABA转运体-1）具有选择性的GABA转运体抑制剂。用刚性双环[3.1.0]己烷主链对3进行进一步的构象限制，成功开发出首个高效且选择性的BGT-1抑制剂4（IC50 = 0.59 μM）。还确定了3对BGT-1的生物活性构象。
