June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
The Synthesis and Testing of Rho Kinase Inhibitors Reversibly Coupled to Corticosteroids for the Treatment of Ocular Inflammatory Diseases
Author Affiliations & Notes
  • Mitchell A. deLong
    Chemistry, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Curtis Kelly
    Biology, Aerie Pharmaceuticals Research and Development, Durham, North Carolina, United States
  • Karen Crews
    Chemistry, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Jill M. Sturdivant
    Chemistry, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Angie Glendenning
    Chemistry, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Briana Foley
    Biology, Aerie Pharmaceuticals Research and Development, Durham, North Carolina, United States
  • Daphne Clancy
    Biology, Aerie Pharmaceuticals Research and Development, Durham, North Carolina, United States
  • Monica Germann
    Chemistry, Aerie Pharmaceuticals Inc, Durham, North Carolina, United States
  • Jeff White
    Biology, Aerie Pharmaceuticals Research and Development, Durham, North Carolina, United States
  • Footnotes
    Commercial Relationships   Mitchell deLong, Aerie Pharmaceuticals (E), Aerie Pharmaceuticals (P); Curtis Kelly, Aerie Pharmaceuticals (E); Karen Crews, Aerie Pharmaceuticals (E); Jill Sturdivant, Aerie Pharmaceuticals (E); Angie Glendenning, Aerie Pharmaceuticals (E); Briana Foley, Aerie Pharmaceuticals (E); Daphne Clancy, Aerie Pharmaceuticals (E); Monica Germann, Aerie Pharmaceuticals (E); Jeff White, Aerie Pharmaceuticals (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 721. doi:
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      Mitchell A. deLong, Curtis Kelly, Karen Crews, Jill M. Sturdivant, Angie Glendenning, Briana Foley, Daphne Clancy, Monica Germann, Jeff White; The Synthesis and Testing of Rho Kinase Inhibitors Reversibly Coupled to Corticosteroids for the Treatment of Ocular Inflammatory Diseases. Invest. Ophthalmol. Vis. Sci. 2021;62(8):721.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Corticosteroids are valuable for controlling ocular inflammation. Their use is limited due to their side effects, including the induction of steroid-induced glaucoma and ocular hypertension (OHT). While the mechanism of this is unclear, fibrosis and excess collagen deposition in the trabecular meshwork (TM) have been described in patients with steroid-induced glaucoma. Compounds that inhibit Rho kinases (ROCK inhibitors) have been shown to reduce deposition of collagen in cultured TM cells. ROCK inhibition also lowers intraocular pressure (IOP) in vivo by increasing aqueous humor TM outflow. We have shown (IOVS 61(7):2953 June 2020) that a rho kinase inhibitor coupled to a corticosteroid reduces inflammation in animal models. To further investigate this new class of molecules, and to optimize activity and stability, a series of novel molecules were synthesized and tested.

Methods : Aerie successfully developed the ROCK inhibitor netarsudil as a treatment for glaucoma (Rhopressa™). Molecules from that research that contain hydroxyl groups were esterified to short chain diacids that were then coupled to steroids. To demonstrate timely enzymatic release of these two moieties, esterase assays have been performed, including with porcine-liver esterase. Retention of ROCK inhibitory activity and steroidal activity were demonstrated in kinase assays and cell lines. Compounds were evaluated for aqueous solubility and stability.

Results : Compounds A-E demonstrated considerable variability in both formulation stability and esterase sensitivity. Multiple compounds displayed potent, often single-digit nM cellular activity in one or more in vitro whole cell assays. Compound A demonstrated an extrapolated stability and activity profile that is suitable for progression. These molecules also demonstrated excellent thermal stability, and sufficient solubility to allow for ophthalmic formulation.

Conclusions : This proprietary class of ROCK inhibitor-linked corticosteroids has demonstrated potent enzymatic and cellular ROCK inhibitory activity, cellular steroidal activity, suitable in vitro and ex vivo metabolism, formulation stability under conditions needed for manufacturing, and anti-inflammatory and IOP-lowering activity in animal models. Compound A in this class of molecules is under further study for the treatment of ocular inflammatory disease.

This is a 2021 ARVO Annual Meeting abstract.

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