Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors
1
External Discovery Chemistry, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States
|
2
Proteros Biostructures GmbH, Bunsenstr. 7a, D-82152 Planegg, Martinsried, Germany
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Publication type: Journal Article
Publication date: 2020-07-15
scimago Q1
wos Q2
SJR: 0.805
CiteScore: 5.8
Impact factor: 4.0
ISSN: 19485875
PubMed ID:
32832022
Organic Chemistry
Drug Discovery
Biochemistry
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.
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70
Total citations:
70
Citations from 2024:
31
(44.93%)
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GOST
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Pu Q. et al. Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors // ACS Medicinal Chemistry Letters. 2020. Vol. 11. No. 8. pp. 1548-1554.
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Yu W., Lammens A., NEUMANN L. Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors // ACS Medicinal Chemistry Letters. 2020. Vol. 11. No. 8. pp. 1548-1554.
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RIS
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TY - JOUR
DO - 10.1021/acsmedchemlett.0c00195
UR - https://doi.org/10.1021/acsmedchemlett.0c00195
TI - Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors
T2 - ACS Medicinal Chemistry Letters
AU - Yu, Wensheng
AU - Lammens, Alfred
AU - NEUMANN, LARS
PY - 2020
DA - 2020/07/15
PB - American Chemical Society (ACS)
SP - 1548-1554
IS - 8
VL - 11
PMID - 32832022
SN - 1948-5875
ER -
Cite this
BibTex (up to 50 authors)
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@article{2020_Pu,
author = {Wensheng Yu and Alfred Lammens and LARS NEUMANN},
title = {Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors},
journal = {ACS Medicinal Chemistry Letters},
year = {2020},
volume = {11},
publisher = {American Chemical Society (ACS)},
month = {jul},
url = {https://doi.org/10.1021/acsmedchemlett.0c00195},
number = {8},
pages = {1548--1554},
doi = {10.1021/acsmedchemlett.0c00195}
}
Cite this
MLA
Copy
Pu, Qinglin, et al. “Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors.” ACS Medicinal Chemistry Letters, vol. 11, no. 8, Jul. 2020, pp. 1548-1554. https://doi.org/10.1021/acsmedchemlett.0c00195.