https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00508
Background:
The Janus Kinase (JAK) family is made up of four structurally related kinases, JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase-2). The JAK family kinases, through the actions of specific cytokines binding to their receptors, are key drivers of immune system and inflammatory responses.
Compound 2 demonstrated efficacy in a pseudoestablished mouse collagen-induced arthritis (mouse CIA) model; however, a dose response was not obtained. Further progression of 2 was also hampered by multiple cardiovascular liabilities, which included hemodynamic effects attributed to inhibition of Rho kinase (ROCK1 IC50 = 50 nM) and the potential for QTc prolongation due to significant inhibition of the hERG ion channel.
Main Text:
Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.
Crystal structure of compound 22 bound to the kinase catalytic domain of JAK3.
Synthesis:
Scheme conditions: (a) (i) NaH, DMF; (ii) Chloramine solution in MTBE (90%); (b) (i) 3,3-diethyoxypropionitrile, IPA, 85 °C; (ii) DBU, DCE, 85 °C (c) POCl3, 75 °C. 29%, 2 steps); (d) Conc. H2SO4, 55 °C (89%); (e) R-NH2; (f) Ar–B(OH)2/Suzuki conditions; (g) EtSH, K2CO3, DMF, rt, 18 h (65%); (h) ArB(OH)2, X-Phos, Pd(OAc)2, 2 M K3PO4, dioxane 125 °C ; (i) oxone, acetone, water; (j) R-NH2, DMF, 85 °C.
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