6B33

Structure of RORgt in complex with a novel inverse agonist 3

Summary for 6B33

• Entry DOI: 10.2210/pdb6b33/pdb
• Descriptor: Nuclear receptor ROR-gamma, (2R)-N~2~-(3-chloro-4-cyanophenyl)-N~4~-[3-(cyclopropylmethyl)-2,4-dioxo-1-(propan-2-yl)-1,2,3,4-tetrahydroquinazolin-6-yl]morpholine-2,4-dicarboxamide (3 entities in total)
• Functional Keywords: complex, inverse agonist, nuclear hormone receptor, signaling protein-antagonist complex, signaling protein/antagonist
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 51902.75

Authors

Skene, R.J.,Hoffman, I.,Snell, G. (deposition date: 2017-09-20, release date: 2018-11-21, Last modification date: 2024-03-13)

Primary citation

Sato, A.,Fukase, Y.,Kono, M.,Ochida, A.,Oda, T.,Sasaki, Y.,Ishii, N.,Tomata, Y.,Fukumoto, S.,Imai, Y.N.,Uga, K.,Shibata, A.,Yamasaki, M.,Nakagawa, H.,Shirasaki, M.,Skene, R.,Hoffman, I.,Sang, B.C.,Snell, G.,Shirai, J.,Yamamoto, S.
Design and Synthesis of Conformationally Constrained ROR gamma t Inverse Agonists.
Chemmedchem, 2019

PubMed Abstract: Retinoic-acid-related orphan receptor γt (RORγt) inverse agonists could be used for the treatment of autoimmune diseases. Previously, we reported a novel quinazolinedione 1 a with a flexible linear linker as a novel RORγt inverse agonist. A U-shaped conformation in the complex structure of 1 a with RORγt protein was confirmed. Further improvement of the pharmacokinetic (PK) profiles was required because of the low drug exposure in mice upon oral administration (mouse AUC of 1 a: 27 ng ⋅ h ⋅ mL at 1 mg ⋅ kg , p.o.). To improve the PK profiles, conformationally constrained U-shaped scaffolds were investigated. As a result, morpholine analogues with improved PK profiles and high potency were successfully identified. The substituent at the N1 position of the quinazoline moiety was also modified, leading to an enhancement of reporter activity. Consequently, compound 43 (N -(3-chloro-4-cyanophenyl)-N -(3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)morpholine-2,4-dicarboxamide) exhibited improved drug exposure (mouse AUC: 1289 ng ⋅ h ⋅ mL at 1 mg ⋅ kg , p.o.). In addition, suppression of IL-17A gene expression by IL-23 stimulation in a mouse pharmacodynamics model was observed for 43. The conformation of 43 with RORγt protein was also confirmed as U-shape by X-ray co-crystal structure analysis. The key interaction that boosts potency is also discussed.

PubMed: 31659845
DOI: 10.1002/cmdc.201900416

Experimental method

X-RAY DIFFRACTION (2.48 Å)