Synthesis and in vitro evaluation of new analogues as inhibitors for phosphodiesterase 10A.

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Zhang Z, Lu X, Xu J, Rothfuss J, Mach RH, Tu Z

Synthesis and in vitro evaluation of new analogues as inhibitors for phosphodiesterase 10A.

Eur J Med Chem. 2011 Sep;46(9):3986-95. doi: 10.1016/j.ejmech.2011.05.072. Epub 2011 Jun 12.

PubMed ID

21705115 [ View in PubMed

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Abstract

A series of analogues were synthesized by optimizing the structure of papaverine. The in vitro PDE10A binding affinity (IC(50)) values for these new analogues were measured; for compounds that have IC(50) value less than 60 nM for PDE10A, the binding affinities (IC(50) value) for PDE3A and PDE3B were tested. Of these analogues, compounds 6a, 6b, 6n, 8b, 8c and 11 displayed relatively higher PDE10A potency with IC(50) value in the range of 28-60 nM. The most potent compound 1-(4-(2-(2-fluoroethoxy)ethoxy)-3-methoxybenzyl)-6,7-dimethoxyisoquinoline (8c) has the IC(50) value of 28 +/- 1.2 nM for PDE10A, 2200 +/- 437 nM for PDE3A and 2520 +/- 210 nM for PDE3B. Compared to papaverine, compound 8c displayed similar PDE10A potency but improved selectivity to PDE10A versus PDE3A and PDE3B. To identify high potent PDE10A inhibitor, further optimization of the structures of these analogues is necessary.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Papaverine	cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A	IC 50 (nM)	21	N/A	N/A	Details