E. Hu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2262–2265
2265
500ꢁ fold improvement in potency, increasing the activity of our
initial lead from IC50 of 590 nM (1) to 1 nM (44, 46). The issue of
high rat in vivo clearance was addressed with installation of alco-
hol substituted cyclic amines (26, 39–41, 43–44, 46). Our selective
inhibitor of PDE10A (39) was demonstrated to be efficacious in a
rodent behavioral model of schizophrenia.
References and notes
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Figure 2. Conditioned Avoidance Response study with compound 39.
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Figure 3. X-ray co-crystal structure of compound 43 in the catalytic domain of
PDE10A enzyme.
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Counterscreen assays showed compounds 39–46 exhibited
350ꢁ–5000ꢁ fold selectivity against PDE3 and several were greater
than 2000ꢁ fold selective against other PDE isomers (1–9, 11) as
well. A co-crystal structure of representative compound 43 in the
human PDE10A catalytic domain elucidated the key bonding inter-
actions (Fig. 3).11 The molecule appeared to be anchored by a bifur-
cating hydrogen bonding interaction between both methoxy groups
on the cinnoline core and the conserved Gln716. The substituents on
the aniline extends to a shelf-like area in the enzyme consisting of
four amino acids: Phe686, Ile701, Met703, and Met704. Comparison
against other phosphodiesterase isozymes revealed that amino acid
residues in this region of the catalytic binding domain differed
amongst the PDEs. Thus, this interaction of the piperidine alcohol
with the PDE10A enzyme in that region was likely the source of its
high selectivity.
10. Wadenberg, M.-L. G.; Hicks, P. B. Neuosci. Biobehav. Rev. 1999, 23, 851.
11. (a) Wang, H.; Liu, Y.; Hou, J.; Zheng, M.; Robinson, H.; Ke, H. Proc. Natl. Acad. Sci.
2007, 104, 5782; (b) Coordinates of co-crystal structure of compound 43 in
PDE10 have been deposited in the Protein Data Bank. PDB ID code is 4DDL.
In conclusion, we have described the identification of a novel,
potent, efficacious and selective inhibitor of PDE10A. Systematic
investigation of structure–activity-relationships resulted in over