DNA Encoded Library Technology-based discovery, lead optimization and prodrug strategy toward structurally-unique indoleamine 2,3-dioxygenase (IDO1) inhibitors.

We report the discovery of a novel IDO1 inhibitor class through the affinity selection of a previously-unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1 had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bioavailable, crystalline 11 was poorly soluble and suffered disappointingly low bioavailability due to solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly-bioavailable phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however, thus a salt screen was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bioavailable crystalline Tris-salt 32. IDO1 inhibitor 32 is characterized by low-calculated human dose, best-in-class potential, and unusual inhibition mode by binding the IDO1 heme-free (apo) form.