TY - JOUR
T1 - Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors
AU - Yang, Hao
AU - Murigi, Francis N.
AU - Wang, Zhijian
AU - Li, Junfeng
AU - Jin, Hongjun
AU - Tu, Zhude
N1 - Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.
PY - 2015/2/15
Y1 - 2015/2/15
N2 - Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6 nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52 ± 0.18, 2.86 ± 0.10, and 3.73 ± 0.60 nM, respectively; these three compounds also showed high in vitro selectivity (>1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain.
AB - Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6 nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52 ± 0.18, 2.86 ± 0.10, and 3.73 ± 0.60 nM, respectively; these three compounds also showed high in vitro selectivity (>1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain.
KW - Benzimidazole analogues
KW - Cinnoline analogues
KW - PET
KW - Phosphodiesterase 10A
UR - http://www.scopus.com/inward/record.url?scp=84922191575&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2014.12.054
DO - 10.1016/j.bmcl.2014.12.054
M3 - Article
C2 - 25592707
AN - SCOPUS:84922191575
SN - 0960-894X
VL - 25
SP - 919
EP - 924
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 4
ER -