New PDE4B selective inhibitors improve inflammatory disease treatments
A UNMC chemist has developed new compounds for the treatment of inflammatory diseases.
These compounds target a protein called phosphodiesterase 4, or PDE4 for short. PDE4 regulates inflammation, and is involved in a number of inflammatory diseases such as chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, atopic dermatitis, inflammatory bowel disease, and central nervous system diseases that include drug addiction, schizophrenia and neurodegenerative diseases.
Several approved drugs currently target PDE4, but with severe side effects—like nausea and vomiting—that limit their use. Many of the current PDE4 inhibitors have poor uptake into the central nervous system which limits their use in the treatment of central nervous system diseases.
UNMC’s new PDE4 inhibitors target a specific isoform of PDE4, the B isoform. Targeting PDE4B should help significantly reduce side effects such as nausea and vomiting.
The new PDE4 inhibitors are designed for increased uptake into the central nervous system, making them more useful than current drugs for treating central nervous system-related inflammatory diseases.
Initial lead compounds exhibit nanomolar potency against PDE4B, an 8-10 fold improved selectivity for PDE4B, and good uptake into the brain. One lead compound has also shown significant improvement in a mouse model of cocaine addiction.
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