Ocular Hypotensive Properties and Biochemical Profile of QLS-101, a Novel ATP-Sensitive Potassium (KATP) Channel Opening Prodrug.
Pervan-Steel Cynthia L, Roy Chowdhury Uttio, Sookdeo Hemchand K, Casale Ralph A, Dosa Peter I, Htoo Thurein M, Fautsch Michael P, Wirostko Barbara M
AI Summary
QLS-101, a novel prodrug, effectively lowered eye pressure in mice for 24 hours after daily topical application, converting to its active form in human eye tissues. This offers a new glaucoma treatment.
Abstract
Purpose
To characterize the ocular hypotensive and pharmacological properties of QLS-101, a novel ATP-sensitive potassium (KATP) channel opening prodrug.
Methods
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).
Results
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.
Conclusions
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.
MeSH Terms
Shields Classification
Key Concepts5
Once-daily topical ocular instillation of 0.2% QLS-101 in C57BL/6J mice (n = 5) resulted in significant (P < 0.01) IOP reductions of 2.1 ± 0.4 mmHg after five days, with a daily attenuation of the effect noted by 23h post-dose.
Once-daily topical ocular instillation of 0.4% QLS-101 in C57BL/6J mice (n = 10) lowered IOP by 4.8 ± 0.7 mm Hg (P < 0.0001), and this effect was sustained for 24 hours.
QLS-101, a novel ATP-sensitive potassium (KATP) channel opening prodrug, failed to induce KATP channel activity in HEK-Kir6.2/SUR2B cells, consistent with its development as a prodrug, while its active moiety, levcromakalim, did induce activity.
In vitro ocular tissue conversion of QLS-101 prodrug to levcromakalim was identified in human iris, ciliary body, trabecular meshwork, and sclera.
Alkaline phosphatase was found to convert QLS-101 to levcromakalim with a mean Km = 630 µM and kcat = 15 min-1.
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