A novel series of cysteine-dependent, allosteric inverse agonists of the nuclear receptor ROR γt.

A novel series of cysteine-dependent, allosteric inverse agonists of the nuclear receptor RORγt. Bioorg Med Chem Lett. 2020 Jan 15;:126967 Authors: Jiang X, Dulubova I, Reisman SA, Hotema M, Lee CI, Liu L, McCauley L, Trevino I, Ferguson DA, Eken Y, Wilson AK, Wigley WC, Visnick M Abstract Inhibition of the nuclear receptor Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a promising strategy for the treatment of autoimmune diseases. In this paper, we describe a series of allosteric, cysteine-dependent, inverse agonists of RORγt. Site-directed mutagenesis and molecular dynamics simulations are supportive of a mechanism of action through specific binding to Cys476 on alpha helix 11 of the ligand binding domain (LBD). Representative compounds in the series selectively inhibit RORγt, potently suppress interleukin-17A (IL-17A) production by human CD4+ T cells, and inhibit T helper 17 (Th17) differentiation from human naïve CD4+ T cells. The advanced compound 13 is orally bioavailable and active at a dose of 3 mg/kg in a murine collagen-induced model of rheumatoid arthritis. Collectively, these data are supportive of the development of compound 13 in autoimmune diseases. PMID: 32005415 [PubMed - as supplied by publisher]
Source: Bioorganic and Medicinal Chemistry Letters - Category: Chemistry Authors: Tags: Bioorg Med Chem Lett Source Type: research