Details

Autor(en) / Beteiligte

• Pu, Qinglin
• Zhang, Hongjun
• Guo, Liangqin
• Cheng, Mangeng
• Doty, Amy C
• Ferguson, Heidi
• Fradera, Xavier
• Lesburg, Charles A
• McGowan, Meredeth A
• Miller, J. Richard
• Geda, Prasanthi
• Song, Xuelei
• Otte, Karin
• Sciammetta, Nunzio
• Solban, Nicolas
• Yu, Wensheng
• Sloman, David L
• Zhou, Hua
• Lammens, Alfred
• Neumann, Lars
• Bennett, David Jonathan
• Pasternak, Alexander
• Han, Yongxin

Titel

Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors

Ist Teil von

• ACS medicinal chemistry letters, 2020-08, Vol.11 (8), p.1548-1554

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2020

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.