Discovery of imidazo[1,5-a]pyrido[3,2-e]pyrazines as a new class of phosphodiesterase 10A inhibitiors.

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Hofgen N, Stange H, Schindler R, Lankau HJ, Grunwald C, Langen B, Egerland U, Tremmel P, Pangalos MN, Marquis KL, Hage T, Harrison BL, Malamas MS, Brandon NJ, Kronbach T

Discovery of imidazo[1,5-a]pyrido[3,2-e]pyrazines as a new class of phosphodiesterase 10A inhibitiors.

J Med Chem. 2010 Jun 10;53(11):4399-411. doi: 10.1021/jm1002793.

PubMed ID

20450197 [ View in PubMed

]

Abstract

Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Mardepodect	cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A	IC 50 (nM)	1.34	N/A	N/A	Details
Papaverine	cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A	IC 50 (nM)	76	N/A	N/A	Details
Papaverine	cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A	IC 50 (nM)	56.9	N/A	N/A	Details