Case 7

Chen et al.30 at Bristol Myers Squibb used a parallel solution- and solid-phase synthetic approach for the discovery and optimization of imidazoquinoxalines as Lck (p56Lck) inhibitors. The protein p56Lck is an Src-like tyrosine kinase that contains five domains (N-terminal, SH3, SH2, kinase, and a noncatalytic C-terminal domain); it is highly expressed in T cells and natural killer (NK) cells, and it plays a critical role in T-cell-mediated immune responses. Because T cells are involved in inflammatory disorders such as rheumatoid arthritis and multiple sclerosis, as well as autoimmune responses (e.g., transplant rejection), Lck inhibition could provide treatments for T-cell-mediated autoimmune and inflammatory disorders.

A high-throughput screening exercise of the Bristol-Myers Squibb compound collection identified 1,5-imidazoquinoxaline 292 as a potent nanomolar selective Lck inhibitor. The authors validated this hit by synthesizing regioisomer 293, where it was determined that regioisomer 292 is indeed the one exhibiting high affinity toward Lck (292: IC50 = 170 nM, 293: IC50 > 50 mM).

The first library (approximately 160 compounds; Scheme 1.33) was made via a parallel solution-phase approach where efforts focused on the exploration of the bromo-phenyl ring of 292. Treating imidazoquinoxalinone 295 with POCl3 afforded the key intermediate 4-chloroimidazo[1,5-a] quinoxaline (296), which was then reacted with a variety of anilines, aminopyridines, phenols, and thiophenols (297). The SAR from this library indicated that removal of the 2-bromo group as well as its replacement with fluoro, methoxy, and nitro groups was deleterious for activity. Removal of the aniline NH or its substitution with O or S was also detrimental for activity. Interestingly, incorporation of an NHCO linker increased potency almost threefold (299: IC50 = 60 nM). Positioning the 2-bromo at the 4-position also resulted in a dramatic loss of activity. However, exchanging the bromo group in 292 with chloro increased potency about threefold (300: IC50 = 60 nM). Surprisingly, it was also found that additional methyl or halo groups (bromide and chloride) at the 6-position increased potency further down to single-digit nanomolar potency (301 to 304: IC50 = 50-9 nM).

First Library (solution phase)

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