期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 11, 期 8, 页码 1548-1554出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00195
关键词
indoleamine-2,3-dioxygenase 1; IDO1; bicyclo[1.1.1]pentane; cancer immunotherapy
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.
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