Structural highlights
Function
PDE10_HUMAN Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.[1]
Publication Abstract from PubMed
The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1mg/kg.
Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.,Burdi DF, Campbell JE, Wang J, Zhao S, Zhong H, Wei J, Campbell U, Shao L, Herman L, Koch P, Jones PG, Hewitt MC Bioorg Med Chem Lett. 2015 May 1;25(9):1864-8. doi: 10.1016/j.bmcl.2015.03.050., Epub 2015 Mar 26. PMID:25863433[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H. Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7. Epub 2007 Mar 26. PMID:17389385
- ↑ Burdi DF, Campbell JE, Wang J, Zhao S, Zhong H, Wei J, Campbell U, Shao L, Herman L, Koch P, Jones PG, Hewitt MC. Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A. Bioorg Med Chem Lett. 2015 May 1;25(9):1864-8. doi: 10.1016/j.bmcl.2015.03.050., Epub 2015 Mar 26. PMID:25863433 doi:http://dx.doi.org/10.1016/j.bmcl.2015.03.050
