title: An effective prodrug strategy to selectively enhance ocular exposure of a cannabinoid receptor (CB1/2) agonist.
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.
authors.affiliation: Novartis Institutes for Biomedical Research , Global Discovery Chemistry, 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Nello
authors.initials: N
authors.lastname: Mainolfi
authors.forename: James
authors.initials: J
authors.lastname: Powers
authors.forename: Jakal
authors.initials: J
authors.lastname: Amin
authors.forename: Debby
authors.initials: D
authors.lastname: Long
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McLaughlin
authors.forename: Bruce
authors.initials: B
authors.lastname: Jaffee
authors.forename: Christopher
authors.initials: C
authors.lastname: Brain
authors.forename: Jason
authors.initials: J
authors.lastname: Elliott
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Sivak
mesh_terms: D000818:Animals; D019540:Area Under Curve; D005123:Eye / Q000378:metabolism / Q000503:physiopathology; D005901:Glaucoma / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate; D008956:Models, Chemical; D015394:Molecular Structure; D009883:Ophthalmic Solutions / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D010539:Permeability; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism
chemical_list: D009883:Ophthalmic Solutions; D011355:Prodrugs; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2