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ID: ALA4680341

Journal: Bioorg Med Chem Lett

Title: 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

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.

CiteXplore: 33422603

DOI: 10.1016/j.bmcl.2021.127778