Qlaris Bio, Inc., Wellesley, Massachusetts, United States.
Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States.
Invest Ophthalmol Vis Sci. 2022 Apr 1;63(4):26. doi: 10.1167/iovs.63.4.26.
To characterize the ocular hypotensive and pharmacological properties of QLS-101, a novel ATP-sensitive potassium (KATP) channel opening prodrug.
Ocular hypotensive properties of QLS-101 were evaluated by measuring IOP with a handheld rebound tonometer after daily topical ocular instillation of 0.2% (n = 5) or 0.4% QLS-101 (n = 10) in C57BL/6J mice. KATP channel specificity was characterized in HEK-293 cells stably expressing human Kir6.2/SUR2B subunits and assessed for off-target interactions using a receptor binding screen. Conversion of QLS-101 prodrug to its active moiety, levcromakalim, was evaluated in vitro using human ocular tissues and plasma samples and after incubation with human phosphatase enzymes (2.0 nM-1.0 µM).
C57BL/6J mice treated once daily with 0.2% QLS-101 exhibited significant (P < 0.01) IOP reductions of 2.1 ± 0.4 mmHg after five days; however, a daily attenuation of the effect was noted by 23h post-dose. By comparison, treatment with 0.4% QLS-101 lowered IOP by 4.8 ± 0.7 mm Hg (P < 0.0001) which was sustained for 24 hours. Unlike levcromakalim, QLS-101 failed to induce KATP channel activity in HEK-Kir6.2/SUR2B cells consistent with its development as a prodrug. No off-target receptor effects were detected with either compound. In vitro ocular tissue conversion of QLS-101 prodrug was identified in human iris, ciliary body, trabecular meshwork, and sclera. Alkaline phosphatase was found to convert QLS-101 (mean Km = 630 µM, kcat = 15 min-1) to levcromakalim.
QLS-101 is a novel KATP channel opening prodrug that when converted to levcromakalim shows 24-hour IOP lowering after once-daily topical ocular administration.
描述一种新型三磷酸腺苷敏感性钾（KATP）通道开放前药 QLS-101 的眼部降压和药理学特性。
通过手持式回弹眼压计测量 C57BL/6J 小鼠每日局部滴注 0.2%（n=5）或 0.4%QLS-101（n=10）后的眼内压，评估 QLS-101 的眼部降压特性。在稳定表达人 Kir6.2/SUR2B 亚基的 HEK-293 细胞中，通过受体结合筛选对 KATP 通道特异性进行特征描述，并评估其与非靶标相互作用。使用人眼组织和血浆样本以及与人类磷酸酶（2.0 nM-1.0 µM）孵育后，评估 QLS-101 前药转化为其活性部分左西孟旦的体外情况。
每天一次用 0.2%QLS-101 治疗的 C57BL/6J 小鼠在五天后表现出明显的（P < 0.01）IOP 降低 2.1 ± 0.4 mmHg，但在 23 小时后观察到剂量效应逐渐减弱。相比之下，用 0.4%QLS-101 治疗降低了 4.8 ± 0.7 mmHg 的 IOP（P < 0.0001），并持续 24 小时。与左西孟旦不同，QLS-101 未能诱导 HEK-Kir6.2/SUR2B 细胞中的 KATP 通道活性，这与其作为前药的开发一致。两种化合物均未检测到非靶标受体作用。在体外，在人虹膜、睫状体、小梁网和巩膜中发现了 QLS-101 前药的转化。碱性磷酸酶被发现将 QLS-101（平均 Km = 630 µM，kcat = 15 min-1）转化为左西孟旦。
QLS-101 是一种新型的 KATP 通道开放前药，局部滴眼每日一次，转化为左西孟旦后可降低 24 小时的眼内压。
