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J Med Chem. 2018 Dec 13;61(23):10412-10414. doi: 10.1021/acs.jmedchem.8b01545. Epub 2018 Dec 3.

A Drug with Lipophilicity-Dependent Potency Can Be Metabolically Stable: Discovery of a Potent and Selective Retinoic Acid Receptor-Related Orphan Receptor C2 (RORC2) Inverse Agonist as an Orally Bioavailable Anti-Inflammatory Agent.

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1
State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.

Abstract

IL-17 drives an amplification mechanism in inflammatory diseases such as psoriasis, psoriatic arthritis, and ankylosing spondylitis. The production of IL-17 depends on the activity of RORC2 in immune cells, which suggests that RORC2 inverse agonists are capable of anti-inflammatory therapy by reducing IL-17 levels. However, oral delivery of inverse agonists remains a challenge since the binding pocket of RORC2 prefers to accommodate lipophilic ligands, which tend to have poor metabolic stability. This Viewpoint discusses recent results published in this journal that identified a potent, selective, and orally bioavailable RORC2 inverse agonist as an anti-inflammatory agent, optimized from a high-throughput screening (HTS) hit through a combination of de novo and structure-guided design.

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