3 research outputs found
Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences
NMR conformational
analysis of a hydroxyethylamine peptide isostere
developed as an aspartic protease inhibitor shows that it is a flexible
architecture. Cyclization to form pyrrolidines, piperidines, or morpholines
results in a preorganization of the whole system in solution. The
resulting conformation is similar to the conformation of the inhibitor
in the active site of BACE-1. This entropic gain results in increased
affinity for the enzyme when compared with the acyclic system. For
morpholines <b>27</b> and <b>29</b>, the combination of
steric and electronic factors is exploited to orient substituents
toward S1, S1′, and S2′ pockets both in the solution
and in the bound states. These highly preorganized molecules proved
to be the most potent compounds of the series. Additionally, the morpholines,
unlike the pyrrolidine and piperidine analogues, have been found to
be brain penetrant BACE-1 inhibitors
Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences
NMR conformational
analysis of a hydroxyethylamine peptide isostere
developed as an aspartic protease inhibitor shows that it is a flexible
architecture. Cyclization to form pyrrolidines, piperidines, or morpholines
results in a preorganization of the whole system in solution. The
resulting conformation is similar to the conformation of the inhibitor
in the active site of BACE-1. This entropic gain results in increased
affinity for the enzyme when compared with the acyclic system. For
morpholines <b>27</b> and <b>29</b>, the combination of
steric and electronic factors is exploited to orient substituents
toward S1, S1′, and S2′ pockets both in the solution
and in the bound states. These highly preorganized molecules proved
to be the most potent compounds of the series. Additionally, the morpholines,
unlike the pyrrolidine and piperidine analogues, have been found to
be brain penetrant BACE-1 inhibitors
Discovery of (1<i>S</i>,2<i>R</i>,3<i>S</i>,4<i>S</i>,5<i>R</i>,6<i>R</i>)‑2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity
As
part of our ongoing efforts to identify novel ligands for the
metabotropic glutamate 2 and 3 (mGlu<sub>2/3</sub>) receptors, we
have incorporated substitution at the C3 and C4 positions of the (1<i>S</i>,2<i>R</i>,5<i>R</i>,6<i>R</i>)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to
generate mGlu<sub>2/3</sub> antagonists. Exploration of this structure–activity
relationship (SAR) led to the identification of (1<i>S</i>,2<i>R</i>,3<i>S</i>,4<i>S</i>,5<i>R</i>,6<i>R</i>)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic
acid hydrochloride (LY3020371·HCl, <b>19f</b>), a potent,
selective, and maximally efficacious mGlu<sub>2/3</sub> antagonist.
Further characterization of compound <b>19f</b> binding to the
human metabotropic 2 glutamate (hmGlu<sub>2</sub>) site was established
by cocrystallization of this molecule with the amino terminal domain
(ATD) of the hmGlu<sub>2</sub> receptor protein. The resulting cocrystal
structure revealed the specific ligand–protein interactions,
which likely explain the high affinity of <b>19f</b> for this
site and support its functional mGlu<sub>2</sub> antagonist pharmacology.
Further characterization of <b>19f</b> in vivo demonstrated
an antidepressant-like signature in the mouse forced-swim test (mFST)
assay when brain levels of this compound exceeded the cellular mGlu<sub>2</sub> IC<sub>50</sub> value