An Effective Prodrug Strategy to Selectively Enhance Ocular Exposure of a Cannabinoid Receptor (CB1/2) Agonist
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- 作者：Nello Mainolfi ; James Powers ; Jakal Amin ; Debby Long ; Wendy Lee ; Margaret E. McLaughlin ; Bruce Jaffee ; Christopher Brain ; Jason Elliott ; Jeremy M. Sivak
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：July 11, 2013
- 年：2013
- 卷：56
- 期：13
- 页码：5464-5472
- 全文大小：491K
- 年卷期：v.56,no.13(July 11, 2013)
- ISSN：1520-4804
文摘
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.