Janus Kinases (JAKs) are intracellular tyrosine kinases which mediate the signaling of cytokines and growth factors involved in the regulation of immunity, inflammation and hematopoiesis. Interest remains high in the identification and development of anti-inflammatory JAK inhibitors that are specific to a single Janus kinase isoform. Non-selective JAK inhibitors that inhibit JAK2 (which mediates EPO and TPO signaling) have the potential to induce anemia and/or thrombocytopenia. A JAK1-selective inhibitor is expected to retain the inhibition of key cytokines (e.g. Type 1 interferons, interferon gamma, IL-4, -5, -13,-31 and -21, while minimizing potential for JAK2-mediated hematopoietic effects.<br/><br/>Using biochemical and cellular assays for screening, we identified a series of JAK1-selective inhibitors from Pfizer’s compound file. Crystallographic data, structure-based drug design and lead-transformation tools were used to optimize the series. Favorable interactions with the P-loop of JAK1 improved JAK1 potency and increased selectivity over JAK2. Several compounds were selected for potential advancement based on JAK1 selectivity, preclinical <i>in vivo</i> efficacy and favorable pharmacokinetics. PF-04965842 is being evaluated in clinical trials for autoimmune disease. Synthetic routes that enabled the delivery of lead preclinical compounds and innovations in chemical synthesis that assured rapid progress of the program through discovery will be highlighted.

Selective JAK1 inhibitors for treatment of inflammatory diseases: Design and synthesis

254th National Meeting (2017)

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