Ohta Masaru, Takahashi Kenji, Kasai Masayasu, Shoji Yoshimichi, Kunishiro Kazuyoshi, Miike Tomohiro, Kanda Mamoru, Mukai Chisato, Shirahase Hiroaki
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., 38 Nishinokyo Tsukinowa-cho, Nakagyo-ku, Kyoto, Japan.
Chem Pharm Bull (Tokyo). 2010 Aug;58(8):1066-76. doi: 10.1248/cpb.58.1066.
To find a novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor with anti-lipid peroxidative activity, a series of tetrahydroisoquinoline derivatives were synthesized and evaluated. A compound with a N-(4-hydroxy-2,3,5-trimethylphenyl)carbamoyl moiety at the 3-position and an octanoyl moiety at the 2-position (7) was demonstrated to show anti-foam cell formation activity stronger than and anti-lipid peroxidative activity comparable to those of Pactimibe, while it was hardly absorbed orally. To increase its bioavailability, the acyl chain at the 2-position was shortened and various polar or basic moieties were introduced at the 7-position of 7. Among the synthesized derivatives, (S)-7-dimethylamino-N-(4-hydroxy-2,3,5-trimethylphenyl)-2-isobutyryl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide hydrochloride (21) showed about 16-fold stronger anti-foam cell formation activity, 3-fold stronger hepatic ACAT inhibitory activity, similar anti-low density lipoprotein (LDL) oxidative activity and 2-fold more potent protective activity against macrophage cell death by oxidative stress in comparison with Pactimibe. Compound 21 was efficiently absorbed after oral administration at 10 mg/kg in rats and dogs and its C(max) values were higher than its IC(50) values for in vitro activities. In conclusion, a tetrahydroisoquinoline structure is a useful scaffold for designing a phenolic anti-oxidative ACAT inhibitor, and compound 21 is expected to effectively prevent atherosclerosis.
为了找到一种具有抗脂质过氧化活性的新型酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂，合成并评估了一系列四氢异喹啉衍生物。结果表明，一种在3位带有N-(4-羟基-2,3,5-三甲基苯基)氨基甲酰基部分且在2位带有辛酰基部分的化合物（7），其抗泡沫细胞形成活性比帕替米贝强，抗脂质过氧化活性与帕替米贝相当，但其口服吸收性较差。为了提高其生物利用度，缩短了2位的酰基链，并在化合物7的7位引入了各种极性或碱性基团。在合成的衍生物中，(S)-7-二甲基氨基-N-(4-羟基-2,3,5-三甲基苯基)-2-异丁酰基-1,2,3,4-四氢异喹啉-3-甲酰胺盐酸盐（21）的抗泡沫细胞形成活性比帕替米贝强约16倍，肝脏ACAT抑制活性强3倍，抗低密度脂蛋白（LDL）氧化活性相似，对氧化应激诱导的巨噬细胞死亡的保护活性比帕替米贝高2倍。化合物21在大鼠和犬中以10 mg/kg口服给药后能有效吸收，其C(max)值高于其体外活性的IC(50)值。总之，四氢异喹啉结构是设计酚类抗氧化ACAT抑制剂的有用骨架，化合物21有望有效预防动脉粥样硬化。
