Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 18, Pages 13807-13829Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01197
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A novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, including compound 20, showed potent inhibition of IL-17A secretion and good metabolic stability in preclinical studies. Compound 20 reduced thymocyte numbers and IL-17A containing gamma delta-T cells, and progressed to phase 1 clinical studies based on favorable safety profile.
Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist 2. Extensive structure-activity relationship (SAR) studies resulted in AZD0284 (20), which combined potent inhibition of IL-17A secretion from primary human T(H)17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical in vivo studies, compound 20 reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing gamma delta-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, 20 was progressed to phase 1 clinical studies.
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