Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-γt (RORγt) agonists.

Authors :: Ruan Z
Park PK
Wei D
Purandare A
Wan H
O'Malley D
Stachura S
Perez H
Cavallaro CL
Weigelt CA
Sack JS
Ruzanov M
Khan J
Gururajan M
Wong JJ
Huang Y
Yarde M
Li Z
Chen C
Sun H
Borowski V
Xie JH
Anthony M
Agler M
Fink BE
Harikrishnan LS
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Mar 01; Vol. 35, pp. 127778. Date of Electronic Publication: 2021 Jan 08.
Publication Year :: 2021
Abstract: The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Subjects :: Animals
Crystallography, X-Ray
Dose-Response Relationship, Drug
Ethers chemical synthesis
Ethers chemistry
Humans
Mice
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Th17 Cells
Tretinoin chemical synthesis
Tretinoin chemistry
Ethers pharmacology
Nuclear Receptor Subfamily 1, Group F, Member 3 agonists
Tretinoin pharmacology

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