Joseph Elisabeth Leenaerts

Discovery of N-(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer’s Disease

A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine 75, a potent and selective tau aggregate binder with potential as a tau PET tracer.

The Synthesis of Trifluoromethyl-sulfonimidamides from Sulfinamides

A general synthesis of CF3-sulfonimidamides from sulfinamides under both batch and continuous flow conditions is described. The reaction proceeds via a sulfonimidoyl fluoride intermediate. A reaction scope showing good group variation on the substituents of both nitrogen atoms is also presented.

Bench-Stable Transfer Reagent Facilitates the Generation of Trifluoromethyl-sulfonimidamides

Sulfonimidamides are an emerging bioisosteric replacement in medicinal chemistry projects, and therefore new chemistries are necessary to access this functionality. The general synthesis of CF3-sulfonimidamides from an activated bench-stable transfer reagent is described. A diverse reaction scope is demonstrated, with a wide range of nucleophilic amines being tolerated in this transformation. The CF3-sulfonimidamides obtained contain an additional diversity point, in the form a protected imine, that could be unmasked to allow late stage modifications.

The discovery and preclinical characterization of 6-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists.

The synthesis, SAR and preclinical characterization of a series of 6-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists is described herein. The lead compounds are potent inhibitors in Ca(2+) flux and whole blood IL-1β P2X7 release assays at both human and mouse isoforms. Compound 1e showed a robust reduction of IL-1β release in a mouse ex vivo model with a 50mg/kg oral dose. Evaluation of compound 1e in the mouse SNI tactile allodynia, carrageenan-induced paw edema or CIA models resulted in no analgesic or anti-inflammatory effects.