Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 13, Pages 5308-5322Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00597
Keywords
-
Categories
Funding
- US NIH Shared Instrumentation grant [S10-RR027172]
Ask authors/readers for more resources
Retinoic acid receptor-related orphan receptor C (ROkc, ROR gamma, or NR1F3) is a nuclear receptor that plays a major role in the production of interleukin (IL)-17. Considerable efforts have been directed toward the discovery of selective RORc inverse agonists as potential treatments of inflammatory diseases such as psoriasis and rheumatoid arthritis. Using the previously reported tertiary sulfonamide 1 as a starting point, we engineered structural modifications that significantly improved human and rat metabolic stabilities while maintaining a potent and highly Selective RORc inverse agonist profile. The most advanced delta-sultam compound, GNE-3500 (27, 1-{4-[3-fluoro-4-(3S,6R)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone), possessed favorable RORc cellular potency with 75-fold selectivity for RORc over other ROR family members and >200-fold selectivity over 25 additional nuclear receptors in a cell assay panel. The favorable potency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependent inhibition of IL-17 in a PR/PD model support the evaluation of 27 in preclinical studies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available