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Mitchell A deLong, Jill Sturdivant, Cynthia Lichorowic, Cheng-Wen Lin, Casey Kopczynski; Effect of Ring Size on the Suitability of a New Class of Rho Kinase Compounds for Posterior Segment Disease. Invest. Ophthalmol. Vis. Sci. 2018;59(9):217.
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© ARVO (1962-2015); The Authors (2016-present)
Kinase inhibitors, particularly inhibitors of rho kinases (ROCKs), lower intraocular pressure in animals and humans. Aerie has developed ROCK inhibitors for the treatment of glaucoma, including Rhopressa™. For posterior segment disorders, ideal physico-chemical properties may differ from those for topical dosing. Novel cyclic kinase inhibitors may have advantages in stability, and solubility. These molecules were designed to be compatible with biodegradable materials for use in intravitreal implants.
Initial studies demonstrated that cyclopropyl linkers between the acid and aryl portions of ROCK inhibitors are superior to acyclic analogs in vitro. To investigate the role that the ring size played in the activity of these molecules a series of differentially-sized analogs were synthesized. Select compounds were tested for ocular hypotensive activity and tolerability in normotensive Dutch Belted rabbits and Formosan Rock monkeys. Active compounds were further screened assess whether inhibition of a second target might contribute to their activity.
Altering ring size and the placement of heteroatoms in the ring structure revealed that some novel molecules possess nanomolar potency at JAK and IKK kinases as well as ROCK. Activity strongly correlated to the geometry of the pendant groups; some modifications that appear minor rendered the molecules almost devoid of activity. Compounds possessed significant manufacturing and storage stability. In addition, a range of solubility was found. In a series of rabbit studies, treatment with derivatives topically produced minimal ΔIOP, upon injection, IOP reductions of up to 7 mm Hg (p<0.01) were observed. The addition of a distal nitrogen atom was critical to achieve nanomolar potency in this class of compounds.
Compounds containing cycloalkyl acid amides continue to be interesting leads for posterior segment disorders, as they display compatibility with common biodegradable polymers and stability under physiological conditions. This class of ROCK inhibitors warrants further study.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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