[Epub ahead of print]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 JM.
Abstract
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.
- PMID:
- 23738526
- [PubMed – as supplied by publisher]
- http://www.ncbi.nlm.nih.gov/pubmed/23738526
