Ocular Hypotensive Properties and Biochemical Profile of QLS-101, a Novel ATP-Sensitive Potassium (KATP) Channel Opening Prodrug

• Published in: Investigative ophthalmology & visual science 2022-04, Vol.63 (4), p.26-26
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Cromakalim; Glaucoma; HEK293 Cells; Humans; KATP Channels; Mice; Mice, Inbred C57BL; Potassium; Prodrugs - pharmacology; Trabecular Meshwork - metabolism
• ISSN: 1552-5783; 0146-0404; 1552-5783
• 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.