title: Minimization of drug-drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators.
abstract: Early lead compounds in this gamma secretase modulator series were found to potently inhibit CYP3A4 and other human CYP isoforms increasing their risk of causing drug-drug-interactions (DDIs). Using structure-activity relationships and CYP3A4 structural information, analogs were developed that minimized this DDI potential. Three of these new analogs were further characterized by rat PK, rat PK/PD and rat exploratory toxicity studies resulting in selection of SPI-1865 (14) as a preclinical development candidate.
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA. Electronic address: jedhubbs@gmail.com.
authors.forename: Jed L
authors.initials: JL
authors.lastname: Hubbs
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Fuller
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors.forename: Wesley F
authors.initials: WF
authors.lastname: Austin
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors.forename: Ruichao
authors.initials: R
authors.lastname: Shen
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ma
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gong
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: McKee
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors.forename: Robyn M B
authors.initials: RM
authors.lastname: Loureiro
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tate
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Dumin
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ives
authors.affiliation: Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Bronk
mesh_terms: D000818:Animals; D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001384:Azetidines; D001688:Biological Products; C000603602:SPI-1865; D013256:Steroids; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: Alzheimer’s disease; Amyloid-beta; Cytochrome P450 3A4; Drug–drug-interactions; Gamma secretase modulator; Natural product; Semisynthesis; Sterol