2 research outputs found
A Scalable Synthesis of the Difluoromethyl-<i>allo</i>-threonyl Hydroxamate-Based LpxC Inhibitor LPC-058
The difluoromethyl-<i>allo</i>-threonyl hydroxamate-based
compound <b>LPC-058</b> is a potent inhibitor of UDP-3-<i>O</i>-(<i>R</i>-3-hydroxymyristoyl)-<i>N</i>-acetylglucosamine deacetylase (LpxC) in Gram-negative bacteria.
A scalable synthesis of this compound is described. The key step in
the synthetic sequence is a transition metal/base-catalyzed aldol
reaction of methyl isocyanoacetate and difluoroacetone, giving rise
to 4-(methoxycarbonyl)-5,5-disubstituted 2-oxazoline. A simple NMR-based
determination of enantiomeric purity is also described
The Importance of Hydrogen Bonding and Aromatic Stacking to the Affinity and Efficacy of Cannabinoid Receptor CB<sub>2</sub> Antagonist, 5‑​(4-​chloro-​3-​methylphenyl)-​1-​[(4-​methylphenyl)methyl]‑​<i>N</i>‑​[(1<i>S</i>,​2<i>S</i>,​4<i>R</i>)‑​1,​3,​3-​trimethylbicyclo[2.2.1]hept-​2-​yl]-​1H-​pyrazole-​3-​carboxamide (SR144528)
Despite
the therapeutic promise of the subnanomolar affinity cannabinoid
CB<sub>2</sub> antagonist, 5-​(4-​chloro-​3-​methylphenyl)-​1-​[(4-​methylphenyl)Âmethyl]-<i>​N</i>-​[(1<i>S</i>,​2<i>S</i>,​4<i>R</i>)-​1,​3,​3-​trimethylbicycloÂ[2.2.1]Âhept-​2-​yl]-​1<i>H</i>-​pyrazole-​3-​carboxamide (SR144528, <b>1</b>), little is known about its binding site interactions and
no primary interaction site for <b>1</b> at CB2 has been identified.
We report here the results of Glide docking studies in our cannabinoid
CB<sub>2</sub> inactive state model that were then tested via compound
synthesis, binding, and functional assays. Our results show that the
amide functional group of <b>1</b> is critical to its CB2 affinity
and efficacy and that aromatic stacking interactions in the TMH5/6
aromatic cluster of CB2 are also important. Molecular modifications
that increased the positive electrostatic potential in the region
between the fenchyl and aromatic rings led to more efficacious compounds.
This result is consistent with the EC-3 loop negatively charged amino
acid, D275 (identified via Glide docking studies) acting as the primary
interaction site for <b>1</b> and its analogues