Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (D.J.B., J.S., B.C.K.); Departments of Chemistry (A.N.S., J.N.J.) and Pharmacology (A.G., W.S.A), and Vanderbilt Institute of Chemical Biology (A.N.S., J.N.J.), Vanderbilt University, Nashville, Tennessee; Pharmaceutical Sciences Research Center, Lipscomb University, Nashville, Tennessee (T.D., W.S.A); and Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (C.R.H.).
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (D.J.B., J.S., B.C.K.); Departments of Chemistry (A.N.S., J.N.J.) and Pharmacology (A.G., W.S.A), and Vanderbilt Institute of Chemical Biology (A.N.S., J.N.J.), Vanderbilt University, Nashville, Tennessee; Pharmaceutical Sciences Research Center, Lipscomb University, Nashville, Tennessee (T.D., W.S.A); and Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (C.R.H.)
J Pharmacol Exp Ther. 2023 Jun;385(3):205-213. doi: 10.1124/jpet.122.001455. Epub 2023 Mar 9.
The unnatural verticilide enantiomer (-verticilide) is a selective and potent inhibitor of cardiac ryanodine receptor (RyR2) calcium release channels and exhibits antiarrhythmic activity in a murine model of catecholaminergic polymorphic ventricular tachycardia (CPVT). To determine verticilide's pharmacokinetic and pharmacodynamic properties in vivo, we developed a bioassay to measure - and -verticilide in murine plasma and correlated plasma concentrations with antiarrhythmic efficacy in a mouse model of CPVT. -Verticilide rapidly degraded in plasma in vitro, showing >95% degradation within 5 minutes, whereas verticilide showed <1% degradation over 6 hours. Plasma was collected from mice following intraperitoneal administration of -verticilide at two doses (3 mg/kg, 30 mg/kg). Peak and area under the plasma-concentration time curve (AUC) scaled proportionally to dose, and the half-life was 6.9 hours for the 3-mg/kg dose and 6.4 hours for the 30-mg/kg dose. Antiarrhythmic efficacy was examined using a catecholamine challenge protocol at time points ranging from 5 to 1440 minutes after intraperitoneal dosing. -Verticilide inhibited ventricular arrhythmias as early as 7 minutes after administration in a concentration-dependent manner, with an estimated potency (IC) of 266 ng/ml (312 nM) and an estimated maximum inhibitory effect of 93.5%. Unlike the US Food and Drug Administration-approved pan-RyR blocker dantrolene, the RyR2-selective blocker -verticilide (30 mg/kg) did not reduce skeletal muscle strength in vivo. We conclude that -verticilide has favorable pharmacokinetic properties and reduces ventricular arrhythmias with an estimated potency in the nanomolar range, warranting further drug development. SIGNIFICANCE STATEMENT: Verticilide has therapeutic potential to treat cardiac arrhythmias, but little is known about its pharmacological profile in vivo. The primary purpose of this study is to determine the systemic exposure and pharmacokinetics of -verticilide in mice and estimate its efficacy and potency in vivo. The current work suggests -verticilide has favorable pharmacokinetic properties and reduces ventricular arrhythmias with an estimated potency in the nanomolar range, warranting further drug development.
unnatural verticilide enantiomer (-verticilide) 是一种选择性和有效的心肌兰尼碱受体 (RyR2) 钙释放通道抑制剂，并在儿茶酚胺多形性室性心动过速 (CPVT) 的小鼠模型中表现出抗心律失常活性。为了确定 verticilide 在体内的药代动力学和药效学特性，我们开发了一种生物测定法来测量小鼠血浆中的 - 和 -verticilide，并将血浆浓度与 CPVT 小鼠模型中的抗心律失常疗效相关联。-Verticilide 在体外的血浆中迅速降解，在 5 分钟内显示 >95%的降解，而 verticilide 在 6 小时内显示 <1%的降解。在腹腔内给予 -verticilide 两种剂量（3mg/kg，30mg/kg）后，从小鼠中收集血浆。峰值和血浆浓度-时间曲线下面积（AUC）与剂量成比例缩放，半衰期分别为 3mg/kg 剂量的 6.9 小时和 30mg/kg 剂量的 6.4 小时。使用儿茶酚胺挑战方案在腹腔给药后 5 至 1440 分钟的时间点检查抗心律失常作用。-Verticilide 以浓度依赖的方式早在给药后 7 分钟就抑制室性心律失常，估计效力（IC）为 266ng/ml（312nM），最大抑制作用估计为 93.5%。与美国食品和药物管理局批准的泛 RyR 阻滞剂 dantrolene 不同，RyR2 选择性阻滞剂 -verticilide（30mg/kg）不会减少体内骨骼肌强度。我们得出的结论是，-verticilide 具有有利的药代动力学特性，以估计在纳米摩尔范围内的效力降低室性心律失常，值得进一步的药物开发。 意义：Verticilide 具有治疗心律失常的治疗潜力，但对其体内药理学特征知之甚少。本研究的主要目的是确定 -verticilide 在小鼠中的全身暴露和药代动力学，并估计其体内疗效和效力。目前的工作表明，-verticilide 具有有利的药代动力学特性，以估计在纳米摩尔范围内的效力降低室性心律失常，值得进一步的药物开发。
