Abstract
Xeljanz (tofacitinib citrate) represents the first in a new class of Janus kinase (JAK) inhibitors for the treatment of rheumatoid arthritis (RA). It operates by modulating the JAK pathways, which play a role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases, including RA. In this case history, we describe the tofacitinib medicinal chemistry journey, starting with lead identification through high-throughput screening, followed by lead development, taking advantage of high-speed analoging and the use of natural products as synthetic building blocks. Finally, optimization of physical properties and pharmacokinetics within a piperidine chemical series led to the selection of CP-690,550 (tofacitinib) as a drug candidate. The selectivity and pharmacology of tofacitinib are described, along with summaries of the preclinical and clinical properties of this drug.
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