Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors
Qinglin Pu, Hongjun Zhang, Liangqin Guo, Mangeng Cheng, Amy C. Doty, Heidi M. Ferguson, Xavier Fradera, Charles A. Lesburg, Meredeth A. McGowan, J. Richard Miller, Prasanthi Geda, Xuelei S. Song, Karin M. Otte, Nunzio Sciammetta, Nicolas Solban, Wensheng Yu, David L. Sloman, Hua Zhou, Alfred Lammens, Lars Neumann, David Jonathan Bennett, Alexander Pasternak, Yongxin Han
Abstract
Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.