| Structural highlights
Function
[I23O1_HUMAN] Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.[1]
Publication Abstract from PubMed
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.
Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors.,Pu Q, Zhang H, Guo L, Cheng M, Doty AC, Ferguson H, Fradera X, Lesburg CA, McGowan MA, Miller JR, Geda P, Song X, Otte K, Sciammetta N, Solban N, Yu W, Sloman DL, Zhou H, Lammens A, Neumann L, Bennett DJ, Pasternak A, Han Y ACS Med Chem Lett. 2020 Jul 15;11(8):1548-1554. doi:, 10.1021/acsmedchemlett.0c00195. eCollection 2020 Aug 13. PMID:32832022[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 2007 Aug 1;67(15):7082-7. PMID:17671174 doi:http://dx.doi.org/10.1158/0008-5472.CAN-07-1872
- ↑ Pu Q, Zhang H, Guo L, Cheng M, Doty AC, Ferguson H, Fradera X, Lesburg CA, McGowan MA, Miller JR, Geda P, Song X, Otte K, Sciammetta N, Solban N, Yu W, Sloman DL, Zhou H, Lammens A, Neumann L, Bennett DJ, Pasternak A, Han Y. Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors. ACS Med Chem Lett. 2020 Jul 15;11(8):1548-1554. doi:, 10.1021/acsmedchemlett.0c00195. eCollection 2020 Aug 13. PMID:32832022 doi:http://dx.doi.org/10.1021/acsmedchemlett.0c00195
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