☆ 4.7 Article

Identification of novel quinazolinedione derivatives as RORγt inverse agonist

BIOORGANIC & MEDICINAL CHEMISTRY (2018)

Journal

BIOORGANIC & MEDICINAL CHEMISTRY

Volume 26, Issue 3, Pages 721-736

Publisher

PERGAMON-ELSEVIER SCIENCE LTD

DOI: 10.1016/j.bmc.2017.12.039

Keywords

ROR gamma t (retinoic acid receptor-related orphan receptor gamma t); Inverse agonist; IL-17; Th17; Quinazolinedione; EAE model

Categories

Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic

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Abstract

Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (ROR gamma t) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule ROR gamma t inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with ROR gamma t protein was also observed. (C) 2017 Elsevier Ltd. All rights reserved.

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