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J Org Chem DOI:10.1021/jo300974j

Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries.

Publication TypeJournal Article
Year of Publication2012
AuthorsLowe, JT, Lee, MD, Akella, LB, Davoine, E, Donckele, EJ, Durak, L, Duvall, JR, Gerard, B, Holson, EB, Joliton, A, Kesavan, S, Lemercier, BC, Liu, H, Marie, J-C, Mulrooney, CA, Muncipinto, G, Welzel-O'Shea, M, Panko, LM, Rowley, A, Suh, B-C, Thomas, M, Wagner, FF, Wei, J, Foley, MA, Marcaurelle, LA
JournalJ Org Chem
Volume77
Issue17
Pages7187-211
Date Published2012 Sep 07
ISSN1520-6904
KeywordsAnimals, Azetidines, Caco-2 Cells, Cell Membrane Permeability, Central Nervous System, Endothelial Cells, Humans, Mice, Molecular Structure, Small Molecule Libraries, Solubility, Spiro Compounds, Stereoisomerism
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.

URLhttp://dx.doi.org/10.1021/jo300974j
DOI10.1021/jo300974j
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22853001?dopt=Abstract

Alternate JournalJ. Org. Chem.
PubMed ID22853001
PubMed Central IDPMC3454511
Grant ListUL1DE019585 / DE / NIDCR NIH HHS / United States
RL1HG004671 / HG / NHGRI NIH HHS / United States
RL1CA133834 / CA / NCI NIH HHS / United States
UL1 DE019585 / DE / NIDCR NIH HHS / United States
RL1GM084437 / GM / NIGMS NIH HHS / United States
P50 GM069721 / GM / NIGMS NIH HHS / United States
RL1 GM084437 / GM / NIGMS NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States
RL1 CA133834 / CA / NCI NIH HHS / United States