title: Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries.
abstract: The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.
authors.affiliation: Chemical Biology Platform, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Lowe
authors.forename: Maurice D
authors.initials: MD
authors.lastname: Lee
authors.forename: Lakshmi B
authors.initials: LB
authors.lastname: Akella
authors.forename: Emeline
authors.initials: E
authors.lastname: Davoine
authors.forename: Etienne J
authors.initials: EJ
authors.lastname: Donckele
authors.forename: Landon
authors.initials: L
authors.lastname: Durak
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.forename: Baudouin
authors.initials: B
authors.lastname: Gerard
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
authors.forename: Adrien
authors.initials: A
authors.lastname: Joliton
authors.forename: Sarathy
authors.initials: S
authors.lastname: Kesavan
authors.forename: Berenice C
authors.initials: BC
authors.lastname: Lemercier
authors.forename: Haibo
authors.initials: H
authors.lastname: Liu
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Marié
authors.forename: Carol A
authors.initials: CA
authors.lastname: Mulrooney
authors.forename: Giovanni
authors.initials: G
authors.lastname: Muncipinto
authors.forename: Morgan
authors.initials: M
authors.lastname: Welzel-O'Shea
authors.forename: Laura M
authors.initials: LM
authors.lastname: Panko
authors.forename: Ann
authors.initials: A
authors.lastname: Rowley
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Suh
authors.forename: Meryl
authors.initials: M
authors.lastname: Thomas
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.forename: Jingqiang
authors.initials: J
authors.lastname: Wei
authors.forename: Michael A
authors.initials: MA
authors.lastname: Foley
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Marcaurelle
mesh_terms: D000818:Animals; D001384:Azetidines / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D012995:Solubility; D013141:Spiro Compounds / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D013237:Stereoisomerism
chemical_list: D001384:Azetidines; D054852:Small Molecule Libraries; D013141:Spiro Compounds; C082735:azetidine