Analogs of the ATP-Sensitive Potassium (K_ATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity

Abstract

KATP channel openers have emerged as potential therapeutics for the treatment of glaucoma, lowering intraocular pressure in animal models and cultured human anterior segments. We have prepared water soluble phosphate and dipeptide derivatives of the KATP channel opener cromakalim and evaluated their IOP lowering capabilities in vivo. In general, the phosphate derivatives proved to be more chemically robust and efficacious at lowering IOP with once daily dosing in a normotensive mouse model. Two of these phosphate derivatives were further evaluated in a normotensive rabbit model, with a significant difference in activity observed. No toxic effects on cell structure or alterations in morphology of the aqueous humor outflow pathway were observed after treatment with the most efficacious compound (3S,4R)−2, suggesting that it is a strong candidate for development as an ocular hypotensive agent.

Pharmacological and pharmacokinetic profile of the novel ocular hypotensive prodrug CKLP1 in Dutch-belted pigmented rabbits

“…CKLP1 and levcromakalim were synthesized in our laboratory as previously described (originally referred to as [3S,4R]-2) [12]. For pharmacokinetic studies, flavopiridol was obtained from the Pharmaceutical Resources Branch of the National Cancer Institute, HPLC grade acetonitrile was from Fisher Scientific (Fairlawn, NJ), analytical grade ammonium formate was from MilliporeSigma (St. Louis, MO), and Captiva 0.2 μm polypropylene 96 well filter plates were from Agilent (Santa Clara, CA).…”

“…Several commercially available K ATP channel openers were shown to lower IOP in ex vivo and in vivo experimental model systems [9][10][11]. Since none of these openers are water-soluble and hence not suitable for human application, we developed an aqueous soluble prodrug based on the structure of levcromakalim [12]. This prodrug, referred to as cromakalim prodrug 1 [CKLP1, chemically referred to as sodium [(3S,4R)-6-cyano-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-chroman-3-yl phosphate] is converted to its active metabolite levcromakalim through in vivo phosphatase cleavage [12].…”

“…Since none of these openers are water-soluble and hence not suitable for human application, we developed an aqueous soluble prodrug based on the structure of levcromakalim [12]. This prodrug, referred to as cromakalim prodrug 1 [CKLP1, chemically referred to as sodium [(3S,4R)-6-cyano-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-chroman-3-yl phosphate] is converted to its active metabolite levcromakalim through in vivo phosphatase cleavage [12]. In animal models, topical treatment of CKLP1 to the eye results in similar IOP reduction as found with levcromakalim [12,13].…”

“…This prodrug, referred to as cromakalim prodrug 1 [CKLP1, chemically referred to as sodium [(3S,4R)-6-cyano-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-chroman-3-yl phosphate] is converted to its active metabolite levcromakalim through in vivo phosphatase cleavage [12]. In animal models, topical treatment of CKLP1 to the eye results in similar IOP reduction as found with levcromakalim [12,13]. Additionally, CKLP1 treatment targets the distal portion of the trabecular outflow pathway leading to reduction of episcleral venous pressure [13].…”

“…Based on the preclinical data [7,[12][13][14], CKLP1 is a promising candidate for clinical investigation in human patients. However, the pharmacologic properties and systemic disposition of CKLP1 and its conversion to levcromakalim are currently unknown.…”