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Papers by Jenna Head
MedChemComm, 2014
PDE1 is a family of calcium-activated, dual substrate phosphodiesterases expressed in both the CN... more PDE1 is a family of calcium-activated, dual substrate phosphodiesterases expressed in both the CNS and periphery that play a role in the integration of intracellular calcium and cyclic nucleotide signaling cascades. Exploration of the potential in targeting this family of enzymes to treat neuropsychiatric disorders has been hampered by a lack of potent, selective, and brain penetrable PDE1 inhibitors. To identify such compounds we used high-throughput screening, structure-based design, and targeted synthetic chemistry to discover the 4-aminoquinazoline 7a (PF-04471141) and the 4-indanylquinazoline 27 (PF-04822163) each of which are PDE1 inhibitors that readily cross the blood brain barrier. These quinazoline-based PDE1-selective inhibitors represent valuable new tools to study the biological processes regulated by PDE1 and to begin to determine the potential therapeutic utility of such compounds to treat neuropsychiatric disorders. † Electronic supplementary information (ESI) available: Broad panel ligand-receptor binding data, PDE1 assay data with standard error, select pharmacokinetic data for 7a and 27, X-ray crystal structure experimental information for 7a and 27, PDE1B1 enzyme purity data and binding assay protocol, and complete synthesis experimental details. The crystal structure of inhibitor 7a bound to the PDE10A catalytic subunit has been deposited to the RCSB protein data bank with the entry code 4NPV. See
MedChemComm, 2014
PDE1 is a family of calcium-activated, dual substrate phosphodiesterases expressed in both the CN... more PDE1 is a family of calcium-activated, dual substrate phosphodiesterases expressed in both the CNS and periphery that play a role in the integration of intracellular calcium and cyclic nucleotide signaling cascades. Exploration of the potential in targeting this family of enzymes to treat neuropsychiatric disorders has been hampered by a lack of potent, selective, and brain penetrable PDE1 inhibitors. To identify such compounds we used high-throughput screening, structure-based design, and targeted synthetic chemistry to discover the 4-aminoquinazoline 7a (PF-04471141) and the 4-indanylquinazoline 27 (PF-04822163) each of which are PDE1 inhibitors that readily cross the blood brain barrier. These quinazoline-based PDE1-selective inhibitors represent valuable new tools to study the biological processes regulated by PDE1 and to begin to determine the potential therapeutic utility of such compounds to treat neuropsychiatric disorders. † Electronic supplementary information (ESI) available: Broad panel ligand-receptor binding data, PDE1 assay data with standard error, select pharmacokinetic data for 7a and 27, X-ray crystal structure experimental information for 7a and 27, PDE1B1 enzyme purity data and binding assay protocol, and complete synthesis experimental details. The crystal structure of inhibitor 7a bound to the PDE10A catalytic subunit has been deposited to the RCSB protein data bank with the entry code 4NPV. See