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 Samano
J. Med. Chem., 2020, 63(7), 3552-3562
https://doi.org/10.1021/acs.jmedchem.9b01799

Abstract

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.