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Abstract #53856 Published in IGR 15-2
An Effective Prodrug Strategy to Selectively Enhance Ocular Exposure of a Cannabinoid Receptor (CB1/2) Agonist
Mainolfi N; Powers J; Amin J; Long D; Lee W; McLaughlin ME; Jaffee B; Brain CT; Elliott J; Sivak JMJournal of Medicinal Chemistry 2013; 0:
Glaucoma is a leading cause of vision loss and blindness, with increased intraocular pressure (IOP) a prominent risk factor. IOP can be efficaciously reduced by administration of topical agents. However, the repertoire of approved IOP-lowering drug classes is limited, and effective new alternatives are needed. Agonism of the cannabinoid receptors CB1/2 significantly reduces IOP clinically, and experimentally. However, development of CB1/2 agonists has been complicated by the need to avoid cardiovascular and psychotropic side effects. Compound A is a potent CB1/2 agonist that is highly excluded from the brain. In a phase I study, compound A eyedrops were well tolerated and generated an IOP-lowering trend, but were limited in dose and exposure due to poor solubility and ocular absorption. Here we present an innovative strategy to rapidly identify compound A prodrugs that are efficiently metabolized to the parent compound, for improved solubility and ocular permeability, while maintaining low systemic exposures.
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Classification:
3.8 Pharmacology (Part of: 3 Laboratory methods)
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
11.16 Vehicles, delivery systems, pharmacokinetics, formulation (Part of: 11 Medical treatment)