Ocular Hypotensive Properties and Biochemical Profile of QLS-101, a Novel ATP-Sensitive Potassium (KATP) Channel Opening Prodrug.
Ocular Hypotensive Properties and Biochemical Profile of QLS-101, a Novel ATP-Sensitive Potassium (KATP) Channel Opening Prodrug.
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DOI：
10.1167/iovs.63.4.26
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发表时间：
2022-04-01
影响因子：
4.4
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中科院分区：
文献类型：
--
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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.
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影响因子：
3.7
作者：
Chowdhury, Uttio Roy;Bahler, Cindy K.;Fautsch, Michael P.
通讯作者：
Fautsch, Michael P.
影响因子：
1.7
作者：
Mehta, Amy A.;Kanu, Levi N.;Edward, Deepak P.
通讯作者：
Edward, Deepak P.
影响因子：
13.7
作者：
Tham, Yih-Chung;Li, Xiang;Cheng, Ching-Yu
通讯作者：
Cheng, Ching-Yu
影响因子：
5.2
作者：
Kers JA;Sharp RE;Defusco AW;Park JH;Xu J;Pulse ME;Weiss WJ;Handfield M
通讯作者：
Handfield M
影响因子：
4.1
作者：
Quigley, HA;Broman, AT
通讯作者：
Broman, AT