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Uttio Roy Chowdhury, Kimberly B Viker, Peter I Dosa, Michael P Fautsch; Ocular hypotensive properties of water soluble prodrugs of the ATP sensitive potassium channel opener cromakalim. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3018. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Our laboratory has shown that several ATP sensitive potassium (KATP) channel openers including cromakalim can lower intraocular pressure (IOP) in normotensive mice and rabbits. Unfortunately commercially available KATP channel openers are only soluble in organics and hence cannot be readily formulated into eye drops for topical administration to humans. To overcome this obstacle, we synthesized multiple prodrugs of cromakalim and evaluated their ocular hypotensive properties in vivo.
Two phosphate conjugated prodrugs (CKLP1, CKLP2) and 3 dipeptide prodrugs (PID37, PID56, PID57) were synthesized from cromakalim. In addition, a more lipophilic analog of CKLP1, CKLP1-CF3, was also prepared. In C57BL/6 mice, drugs were topically applied at 2.5 or 5 mM (in PBS, once daily for 5 days) in one eye while contralateral eye received vehicle (PBS) only. IOP was measured with a rebound tonometer 1, 4 and 23 hours after each drug application and the three readings were averaged and recorded as the daily IOP. CKLP1 and CKLP1-CF3 were further evaluated in Dutch-belted pigmented rabbits using the same experimental design performed in mice. Student’s paired t-test was used for statistical calculations and significance determination (p<0.05).
Water-soluble phosphate conjugated cromakalim derivatives CKLP1 (2.5 mM), CKLP2 (2.5 mM) and CKLP1-CF3 (5 mM) lowered IOP in mice by 2.99 ± 0.4 mmHg (n=10, p<0.005), 1.60 ± 0.43 mmHg (n=5, p<0.005) and 3.92 ± 0.32 mmHg (n=10, p<0.005). These reductions are similar to IOP lowering effects of cromakalim (3.19 ± 0.41 mmHg, n=10, p<0.005). Dipeptide prodrugs PID37 (5 mM), PID56 (5 mM) and PID57 (5 mM) lowered IOP in mice by 1.52 ± 0.45 mmHg (n=5, p<0.005), 2.60 ± 0.39 mmHg (n=10, p<0.005) and 1.25 ± 0.46 mmHg (n=5, p<0.005). However these compounds showed a reduced stability profile compared to the phosphate conjugated cromakalim prodrugs. In rabbits, CKLP1 (5 mM) lowered IOP by 2.40 ± 0.50 mmHg (n=10, p<0.001). CKLP1-CF3 (5 mM) was less effective in rabbits, lowering IOP by 1.60 ± 0.52 mmHg (n=5 p<0.005).
All cromakalim prodrugs lowered IOP significantly. However, CKLP1 demonstrated the best combination of chemical stability and efficacy at lowering IOP in both mice and rabbits.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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