Starting with cyclopropyl amide lead 2 , identified through a hit to lead (H2L) effort, we were able to improve TYK2 potency and selectivity against JAK1-3 isoforms. More importantly, improved potency and selectivity was achieved without compromising the excellent ligand efficiency and ADME properties of the original lead 2 . Systematic SAR efforts led to (1R, 2R)-cis-F-cyclopropyl amide 3 , which was cellularly potent, selective, and showed dose-dependent knockdown of IL-12 pathway in a mouse PK/PD model.

Lead optimization of a TYK2 selective scaffold

243rd National Meeting (2012)

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