jm9b01799_si_001.pdf (1.88 MB)
DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors
journal contribution
posted on 2020-03-19, 17:07 authored by Wieslaw M. Kazmierski, Bing Xia, John Miller, Martha De la Rosa, David Favre, Richard M. Dunham, Yoshiaki Washio, Zhengrong Zhu, Feng Wang, Makda Mebrahtu, Hongfeng Deng, Jonathan Basilla, Liping Wang, Ghotas Evindar, Lijun Fan, Alison Olszewski, Ninad Prabhu, Christopher Davie, Jeffrey A. Messer, Vicente SamanoWe 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.