期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 30, 期 12, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2020.127205
关键词
Retinoid-related orphan receptor gamma t; RORc; RORgt; Thiazole; Inverse agonist
The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. ROR gamma t lies at the core of this pathway and represents an attractive opportunity for intervention with small molecule therapeutics. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of ROR gamma t drug discovery. We recently described the discovery and evaluation of a new class of potent and selective ROR gamma t inverse agonists based on a thiazole scaffold. Herein we describe the successful optimization of this class by incorporation of an additional amide moiety at the 4-position of the thiazole core. In several optimization cycles, we have reduced human PXR activation, improved solubility, and increased potency while maintaining nuclear receptor selectivity. X-ray crystallographic analysis of compound lg bound in the sterol binding site of the ligand binding domain of ROR gamma t was largely consistent with an earlier structure, guiding further insight into the molecular mechanism for ROR gamma t inhibition with this series. Compound 1g is orally bioavailable, potent in a human whole blood assay and proved to be efficacious in an ex-vivo IL-17A assay, and was selected for preclinical evaluation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据