Background: Janus kinase 3 (Jak3) inhibitors hold promise for treatment of autoimmunity, but developing selective inhibitors is challenging. Results: We designed Jak3 inhibitors that avoid inhibition of the other JAKs. Conclusion: Our inhibitors possess high selectivity against other kinases and can potently inhibit Jak3 activity in cell-based assays. Significance: This class of irreversible inhibitors may be useful as selective agents of Jak3 inhibition.
Glucocorticoid
receptor modulators (GRM) are the first-line treatment
for many immune diseases, but unwanted side effects restrict chronic
dosing. However, targeted delivery of a GRM payload via an immunology
antibody–drug conjugate (iADC) may deliver significant efficacy
at doses that do not lead to unwanted side effects. We initiated our
α-TNF-GRM ADC project focusing on identifying the optimal payload
and a linker that afforded stable attachment to both the payload and
antibody, resulting in the identification of the synthetically accessible
maleimide-Gly-Ala-Ala linker. DAR 4 purified ADCs were shown to be
more efficacious in a mouse contact hypersensitivity model than the
parent α-TNF antibody. Analysis of P1NP and corticosterone biomarkers
showed there was a sufficient therapeutic window between efficacy
and unwanted effects. In a chronic mouse arthritis model, α-TNF-GRM
ADCs were more efficacious than both the parent α-TNF mAb and
an isotype control bearing the same GRM payload.
S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris, 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam , , AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29 improves blood-brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood-brain barrier such as Alzheimer's disease or multiple sclerosis.
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