Details

Autor(en) / Beteiligte

• Chakka, Nagasree
• Andrews, Kristin L.
• Berry, Loren M.
• Bregman, Howard
• Gunaydin, Hakan
• Huang, Liyue
• Guzman-Perez, Angel
• Plant, Matthew H.
• Simard, Jeffrey R.
• Gingras, Jacinthe
• DiMauro, Erin F.

Titel

Applications of parallel synthetic lead hopping and pharmacophore-based virtual screening in the discovery of efficient glycine receptor potentiators

Ist Teil von

• European journal of medicinal chemistry, 2017-09, Vol.137, p.63-75

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• Glycine receptors (GlyRs) are pentameric glycine-gated chloride ion channels that are enriched in the brainstem and spinal cord where they have been demonstrated to play a role in central nervous system (CNS) inhibition. Herein we describe two novel classes of glycine receptor potentiators that have been developed using similarity- and property-guided scaffold hopping enabled by parallel synthesis and pharmacophore-based virtual screening strategies. This effort resulted in the identification of novel, efficient and modular leads having favorable in vitro ADME profiles and high CNS multi-parameter optimization (MPO) scores, exemplified by azetidine sulfonamide 19 and aminothiazole sulfone (ent2)-20. [Display omitted] •GlyRs represent promising but highly challenging targets for pain.•Very few positive modulators with acceptable lead-like properties are known.•Two novel and efficient potentiator classes were discovered.•Property-guided scaffold hop; structure-guided pharmacophore-based virtual screen.•Property- and metabolism-guided hit-to-lead drove improved azetidine sulfonamides.