Michiel Luc Maria Van Gool

Rational design and synthesis of aminopiperazinones as β-secretase (BACE) inhibitors.

Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.

A Versatile Approach to CF3‐Containing 2‐Pyrrolidones by Tandem Michael Addition–Cyclization: Exemplification in the Synthesis of Amidine Class BACE1 Inhibitors

The synthesis of new fluorinated pyrrolidones starting from unprotected amino esters and amino nitriles through a Michael addition-lactamization sequence is described. The resulting CF3 -containing building blocks, bearing a quaternary stereogenic center adjacent to the fluorinated group, have been converted into amino pyrrolidines that display potent β-secretase 1 (BACE1) inhibitory activity. This work constitutes an example of selective fluorination as a valid strategy for the modulation of physicochemical and biological properties of lead compounds in drug discovery.

Diastereoselective Synthesis of 2-Phenyl-3-(trifluoromethyl)piperazines as Building Blocks for Drug Discovery

The synthesis of enantiomerically pure cis- and trans-2-phenyl-3-(trifluoromethyl)piperazines is described. It involved, as the key step, a diastereoselective nucleophilic addition of the Ruppert-Prakash reagent (TMSCF3) to α-amino sulfinylimines bearing Ellmans auxiliary. This methodology allows an entry into hitherto unknown trifluoromethylated and stereochemically defined piperazines, key scaffold components in medicinal chemistry.

1,3,5-Trisubstituted Pyrazoles as Potent Negative Allosteric Modulators of the mGlu2/3 Receptors

The metabotropic glutamate subtype 2 (mGlu2) receptor is a presynaptic membrane receptor distributed widely in brain that provides feedback inhibitory control of glutamate release. Inhibition of the mGlu2 receptor function with a negative allosteric modulator (NAM) enhances activity‐dependent glutamate release, which may be of therapeutic benefit for the treatment of neurological and psychiatric disorders. An attractive pyrazole hit was identified after a high‐throughput screening (HTS) campaign. The evolution of this hit is described by structure–activity relationship (SAR) studies on specific parts of the molecule. From near micromolar potency we could obtain compounds with single‐digit nanomolar activity in the mGlu2 NAM GTPγS assay. In addition to SAR on in vitro potency, a more detailed overview is given with a specific set of compounds on the excellent agreement between in vitro potency, free brain concentration, and ex vivo mGlu2 receptor occupancy. Finally, to obtain improved drug‐like compounds, plans for future research are suggested toward increasing free brain concentration while maintaining high in vitro potency.