Watanuki Susumu, Matsuura Keisuke, Tomura Yuichi, Okada Minoru, Okazaki Toshio, Ohta Mitsuaki, Tsukamoto Shin-ichi
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan.
Chem Pharm Bull (Tokyo). 2012;60(2):223-34. doi: 10.1248/cpb.60.223.
We synthesized and evaluated the inhibitory activity of a series of 2-(1-alkylpiperidin-4-yl)-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide derivatives against T-type Ca(2+) channels. Structure-activity relationship studies revealed that the position of the amide structure was important for the potent inhibitory activity toward T-type Ca(2+) channels. In addition, the introduction of an appropriate substituent on the pendant benzene ring played a crucial role for the selectivity towards T-type Ca(2+) channels over L-type Ca(2+) channels and the potent bradycardic activity of these derivatives. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-2-(1-{2-[2-(2-methoxyethoxy)phenyl]ethyl}piperidin-4-yl)acetamide (4f), which had superior selectivity for T-type Ca(2+) channels over L-type Ca(2+) channels, lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.
我们合成并评估了一系列2-(1-烷基哌啶-4-基)-N-[(1R)-1-(4-氟苯基)-2-甲基丙基]乙酰胺衍生物对T型Ca(2+)通道的抑制活性。构效关系研究表明，酰胺结构的位置对于对T型Ca(2+)通道的强效抑制活性很重要。此外，在苯环侧链上引入合适的取代基对于这些衍生物对T型Ca(2+)通道相对于L型Ca(2+)通道的选择性以及强效的心动过缓活性起着关键作用。口服对T型Ca(2+)通道相对于L型Ca(2+)通道具有更高选择性的N-[(1R)-1-(4-氟苯基)-2-甲基丙基]-2-(1-{2-[2-(2-甲氧基乙氧基)苯基]乙基}哌啶-4-基)乙酰胺(4f)，可降低自发性高血压大鼠的血压，且不会诱发传统L型Ca(2+)通道阻滞剂常引起的反射性心动过速。
