Abstract：
:GSK805 (1) is a potent RORγt inverse agonist, but a drawback of 1 is its low solubility, leading to a limited absorption in high doses. We have explored detailed structure-activity relationship on the amide linker, biaryl and arylsulfonyl moieties of 1 trying to improve solubility while maintaining RORγt activity. As a result, a novel series of carboxyl-containing biaryl urea derivatives was discovered as potent RORγt inverse agonists with improved drug-like properties. Compound 3i showed potent RORγt inhibitory activity and subtype selectivity with an IC50 of 63.8 nM in RORγ FRET assay and 85 nM in cell-based RORγ-GAL4 promotor reporter assay. Reasonable inhibitory activity of 3i was also achieved in mouse Th17 cell differentiation assay (76% inhibition at 0.3 μM). Moreover, 3i had greatly improved aqueous solubility at pH 7.4 compared to 1, exhibited decent mouse PK profile and demonstrated some in vivo efficacy in an imiquimod-induced psoriasis mice model.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Sun N,Huang Y,Yu M,Zhao Y,Chen JA,Zhu C,Song M,Guo H,Xie Q,Wang Ydoi
10.1016/j.ejmech.2020.112536subject
Has Abstractpub_date
2020-09-15 00:00:00pages
112536eissn
0223-5234issn
1768-3254pii
S0223-5234(20)30508-0journal_volume
202pub_type
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