Medicinal chemistry perspective of JAK inhibitors: synthesis, biological profile, selectivity, and structure activity relationship

JAK-STAT signalling pathway was discovered more than quarter century ago. The JAK-STAT pathway protein is considered as one of the crucial hubs for cytokine secretion which mediates activation of different inflammatory, cellular responses and hence involved in different etiological factors. The various etiological factors involved are haematopoiesis, immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis. The presence of the active mutation V617K plays a significant role in the progression of the JAK-STAT pathway-related disease. Consequently, targeting the JAK-STAT pathway could be a promising therapeutic approach for addressing a range of causative factors. In this current review, we provided a comprehensive discussion for the in-detail study of anatomy and physiology of the JAK-STAT pathway which contributes structural domain rearrangement, activation, and negative regulation associated with the downstream signaling pathway, relationship between different cytokines and diseases. This review also discussed the recent development of clinical trial entities. Additionally, this review also provides updates on FDA-approved drugs. In the current investigation, we have classified recently developed small molecule inhibitors of JAK-STAT pathway according to different chemical classes and we emphasized their synthetic routes, biological evaluation, selectivity, and structure–activity relationship.

The JAK-STAT pathway is mainly involved in pathological conditions such as Rheumatoid arthritis, Parkinson’s disease, Atopic dermatitis, Myeloproliferative neoplasm, T-cell leukaemia, Systemic lupus erythematosus, Haematological malignancies, and Idiopathic pulmonary fibrosis. The development of JAK-STAT pathway inhibitors mainly focusses on the inhibition of those diseased conditions. The in-depth review mainly describes the synthetic scheme, structure activity relationship, selectivity and biological activity of globally approved drugs along with recent development of small molecule inhibitors containing different heterocyclic scaffolds (pyridine, pyrimidine, imidazole, indole, pyrazole, pyrrole and triazine).