Modulation of JAK/STAT signaling is a promising method of treating autoimmune disease. Questions pertinent to this approach concern the ideal selectivity between JAK1 and JAK3, which cells are most relevant and the ideal distribution pattern for addressing specific autoimmune conditions. JAK3 specific inhibitors (high quality probes, FM-381) were created by targeting C909 near the ATP binding site by our group. These compounds are highly selective and distributed by the Structural Genomic Consortium as “best available probe”, however, these are limited in uptake and exposure in vivo. There is still a high need for higjlyhighly JAK3- selective probes with good in vivo / ADME properties. A restriction of the FM-series appears to be metabolic instability of side groups addressing the selectivity pocket. This can be compensated by employing cyclopropyl or phenyl residues, however, at the cost of affinity. Through optimizing pharmacokinetic properties, we identified derivates with improved stability and tissue exposure. Conjugation to macrolide scaffolds with medium chain linkers was sufficient to stabilize the compounds and improve transport to organs while maintaining JAK3 affinity. These conjugates are inflammation targeted JAK3 inhibitors with long tissue half-lives and high exposure to activated immune cells. In summary, oral bioavailability could be improved up to 46% and half-life up to 180 min (mice) with good organ distribution.

Pharmacokinetic optimization of small molecule JAK3 inhibitors and macrolide conjugates thereof

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.