Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 6, Pages 1221-1227Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00063
Keywords
ROR gamma t; RORc; inverse agonist; IL-17; IL-23R; psoriasis
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Novel tricyclic analogues were designed, synthesized, and evaluated as ROR gamma t inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.
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