Open AccessUtilization of Metabolite Identification and Structural Data to Guide Design of Low-Dose IDO1 Inhibitors
Author(s) -
Brett A. Hopkins,
Hongjun Zhang,
Indu Bharathan,
Derun Li,
Qinglin Pu,
Hua Zhou,
Theodore A. Martinot,
Xavier Fradera,
Alfred Lammens,
Charles A. Lesburg,
Ryan D. Cohen,
Jeanine Ballard,
Ian Knemeyer,
Karin Otte,
Stella Vincent,
J. Richard Miller,
Nicolas Solban,
Mangeng Cheng,
Prasanthi Geda,
Nadya Smotrov,
Xuelei S. Song,
David Jonathan Bennett,
Yongxin Han
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00265
Subject(s) - potency , metabolic stability , cyclopropane , metabolite , pharmacology , pharmacokinetics , chemistry , identification (biology) , computational biology , stereochemistry , medicine , combinatorial chemistry , biochemistry , in vitro , biology , organic chemistry , botany , ring (chemistry)
Herein the discovery of potent IDO1 inhibitors with low predicted human dose is discussed. Metabolite identification (MetID) and structural data were used to strategically incorporate cyclopropane rings into this tetrahydronaphthyridine series of IDO1 inhibitors to improve their metabolic stability and potency. Enabling synthetic chemistry was developed to construct these unique fused cyclopropyl compounds, leading to inhibitors with improved pharmacokinetics and human whole blood potency and a predicted human oral dose as low as 9 mg once daily (QD).