6-(Ar)Alkylamino-Substituted Uracil Derivatives: Lipid Mimetics with Potent Activity at the Orphan G Protein-Coupled Receptor 84 (GPR84)

ACS Omega
Thanigaimalai PillaiyarChrista E Müller

Abstract

GPR84, a Gi protein-coupled receptor that is activated by medium-chain (hydroxy)fatty acids, appears to play an important role in inflammation, immunity, and cancer. Recently, 6-octylaminouracil (4) has been reported to act as an agonist at GPR84. Here, we describe the synthesis of 69 derivatives and analogs of 4, 66 of which represent new compounds. They were evaluated in (a) cyclic adenosine monophosphate accumulation and (b) β-arrestin assays in human GPR84-expressing cells. Potent nonbiased as well as G protein-biased agonists were developed, e.g., 6-hexylamino-2,4(1H,3H)-pyrimidinedione (20, PSB-1584, EC50 5.0 nM (a), 3.2 nM (b), bias factor: 0) and 6-((p-chloro- and p-bromo-phenylethyl)amino)-2,4(1H,3H)-pyrimidinedione (47, PSB-16434, EC50 7.1 nM (a), 520 nM (b), bias factor: 1.9 = 79-fold Gi pathway-selective; 48, PSB-17365, EC50 2.5 nM (a), 100 nM (b), bias factor 1.3 = 20-fold selective), which were selective versus other free fatty acid-activated receptors. Compounds 20 and 48 were found to be metabolically stable upon incubation with human liver microsomes. A pharmacophore model was created on the basis of structurally diverse lipidlike GPR84 agonists.

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Citations

Sep 7, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·William L TurnbullLeonard G Luyt
Sep 2, 2020·British Journal of Pharmacology·Sara MarsangoGraeme Milligan
Oct 2, 2020·DNA and Cell Biology·Vincent B LuscombeDavid R Greaves
Feb 14, 2019·Scientific Reports·Sarah J ManciniGraeme Milligan
Oct 30, 2020·Cells·Jesús Cosín-RogerSara Calatayud
Feb 14, 2021·International Journal of Molecular Sciences·Manuel GrundmannFrank Eitner
Dec 4, 2020·Journal of Medicinal Chemistry·Lin-Hai ChenFa-Jun Nan

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Methods Mentioned

BETA
homogeneous
NMR
column chromatography
Assay

Software Mentioned

GraphPad Prism
MOE
Prism
PathHunter
Molecular Operating Environment ( MOE
DiscoverX

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