An Effective Prodrug Strategy to Selectively Enhance Ocular Exposure of a Cannabinoid Receptor (CB1/2) Agonist
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Mainolfi, Nello, Powers, James, Amin, Jakal, Long, Debby, Lee, Wendy, Mclaughlin, Margaret, Jaffee, Bruce, Brain, Christopher, Elliott, Jason and Sivak, Jeremy (2013) An Effective Prodrug Strategy to Selectively Enhance Ocular Exposure of a Cannabinoid Receptor (CB1/2) Agonist. Journal of Medicinal Chemistry. ISSN 0022-2623
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. 1 is a potent CB1/2 agonist that is highly excluded from the brain. In a phase I study, compound 1 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 1 prodrugs that are efficiently metabolized to the parent compound, for improved solubility and ocular permeability, while maintaining low systemic exposures.
| Item Type: | Article |
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| Keywords: | CB1/2 Agonists, Glaucoma, Prodrug, Cornea |
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| Date Deposited: | 13 Oct 2015 13:13 |
| Last Modified: | 13 Oct 2015 13:13 |
| URI: | https://oak.novartis.com/id/eprint/9669 |