DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors

We report the discovery
of a novel indoleamine 2,3-dioxygenase-1
(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 bio-available, crystalline 11 was
poorly soluble and suffered disappointingly low bio-availability because
of solubility-limited absorption. A prodrug approach was deployed
and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining
crystalline 31 proved problematic, however; thus salt
screening was performed in an attempt to circumvent this obstacle
and successfully delivered greatly soluble and bio-available crystalline
tris-salt 32. IDO1 inhibitor 32 is characterized
by a low calculated human dose, best-in-class potential, and an unusual
inhibition mode by binding the IDO1 heme-free (apo) form.