6b33

Publication Abstract from PubMed

Retinoic-acid-related orphan receptor gammat (RORgammat) inverse agonists could potentially be used for the treatment of autoimmune diseases. Previously, we reported a novel quinazolinedione 1a with a flexible linear linker as a novel RORgammat inverse agonist. A U-shaped conformation in the complex structure of 1a with RORgammat 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 1a : 27 ng*h/mL at 1 mg/kg, po). To improve the PK profiles, conformationally constrained U-shaped scaffolds were investigated. As a result, morpholine analogs with improved PK profiles and high potency were successfully identified. The substituent on the N1-position of the quinazoline moiety was also modified, leading to an enhancement of reporter activity. Consequently, compound 43 exhibited improved drug exposure (mouse AUC: 1289 ng*h/mL at 1 mg/kg, po). 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 RORgammat protein was also confirmed as U-shape by X-ray co-crystal structure analysis. The key interaction that boosts potency is also discussed.

Design and Synthesis of Conformationally Constrained RORgammat Inverse Agonists.,Sato A, Fukase Y, Kono M, Ochida A, Oda T, Sasaki Y, Ishii N, Tomata Y, Fukumoto S, Imai YN, Uga K, Shibata A, Yamasaki M, Nakagawa H, Shirasaki M, Skene R, Hoffman I, Sang BC, Snell G, Shirai J, Yamamoto S ChemMedChem. 2019 Oct 28. doi: 10.1002/cmdc.201900416. PMID:31659845^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.