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Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1). | LitMetric

Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1).

ACS Med Chem Lett

Department of Chemistry, Computational and Structural Chemistry, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.

Published: April 2020

AI Article Synopsis

Article Abstract

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1. While hit possessed attractive cell-based potency, it suffered from a significant right-shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-based approach, including a focus on lowering AlogP via the strategic introduction of polar substitution, compound was identified bearing a pyridyl oxetane core. Compound demonstrated improved whole blood potency and solubility, and an improved pharmacokinetic profile resulting in a low predicted human dose.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153270PMC
http://dx.doi.org/10.1021/acsmedchemlett.0c00010DOI Listing

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