title: Caprospinol: moving from a neuroactive steroid to a neurotropic drug.
abstract: In search of new drugs for Alzheimer's disease, we departed from the classic concepts and investigated the ability of normal and Alzheimer's disease brain to convert cholesterol to steroids, otherwise known as neurosteroids. We identified 22R-hydroxycholesterol to be present in much lower levels in the hippocampus and frontal cortex of Alzheimer's disease than in tissue from age-matched controls. 22R-hydroxycholesterol was shown to protect against beta-amyloid (A beta(42))-induced neurotoxicity and block the formation of A beta oligomers. In search of a 22R-hydroxycholesterol stable analog, we identified the naturally occurring heterospirostenol, (22R,25R)-20 alpha-spirost-5-en-3beta-yl hexanoate (caprospinol). The mechanism of action underlying the neuroprotective properties of caprospinol involves, first, the ability of the compound to bind A beta(42) and, second, its interaction with components of the mitochondria respiratory chain. Samaritan Pharmaceuticals is developing caprospinol as a disease-modifying drug for the treatment of Alzheimer's disease. Samaritan Pharmaceuticals filed for an Investigational New Drug application with the FDA in 2006. The pharmacokinetic and pharmacodynamic parts of the application were found satisfactory, and the FDA has requested that additional information is submitted in support of caprospinol's safety prior to initiating the Phase I clinical study.
authors.affiliation: McGill University Health Centre, The Research Institute of the McGill University Health Centre, 6100 Royalmount Avenue, Montreal, Quebec, H4P 2R2, Canada. laurent.lecanu@mcgill.ca
authors.forename: Laurent
authors.initials: L
authors.lastname: Lecanu
authors.forename: Laurent
authors.initials: L
authors.lastname: Tillement
authors.forename: Georges
authors.initials: G
authors.lastname: Rammouz
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Tillement
authors.forename: Janet
authors.initials: J
authors.lastname: Greeson
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadopoulos
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002208:Caproates; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D013150:Spirostans; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C514145:(22R, 25R)-20alpha-spirost-5-en-3beta-yl hexanoate; D000682:Amyloid; D002208:Caproates; D013150:Spirostans; D013256:Steroids; D004144:Diosgenin