John Emmerson Campbell
Sunovion
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Publication
Featured researches published by John Emmerson Campbell.
Bioorganic & Medicinal Chemistry Letters | 2011
Liming Shao; Michael Charles Hewitt; Fengjiang Wang; Scott Christopher Malcolm; Jianguo Ma; John Emmerson Campbell; Una Campbell; Sharon Rae Engel; Nancy A. Spicer; Larry W. Hardy; Rudy Schreiber; Kerry L. Spear; Mark A. Varney
The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC(50)=169, 85, 21 nM) and 42 (SERT, NET, DAT IC(50)=34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.
Pharmacology, Biochemistry and Behavior | 2015
Philip Jones; Michael Charles Hewitt; John Emmerson Campbell; Maria S. Quinton; Sharon Rae Engel; Robert A. Lew; Una C. Campbell; Douglas F. Burdi
In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0nM) inhibitor of human PDE10A in vitro, with good selectivity (>16000-fold) against other PDEs. In an in vivo occupancy study, the RO50 value was determined to be 0.7mg/kg (p.o.), corresponding to plasma and brain exposures of 28ng/mL and 43ng/g, respectively. Using microdialysis, we show that 3mg/kg (p.o.) SEP-39 significantly increased rat striatal cGMP concentrations. Furthermore, SEP-39 inhibits PCP-induced hyperlocomotion at doses of 1 and 3mg/kg (p.o.) corresponding to 59-86% occupancy. At similar doses in a catalepsy study, the time on the bar was increased but the maximal effect was less than that seen with haloperidol. In an EEG study, 3 and 10mg/kg (p.o.) SEP-39 suppressed REM intensity and increased the latency to REM sleep. We also demonstrate the procognitive effects of SEP-39 in the rat novel object recognition assay. These effects appear to require less PDE10A inhibition than the reversal of PCP-induced hyperlocomotion or EEG effects, as improvements in recognition index were seen at doses of 0.3mg/kg and above. Our data demonstrate that SEP-39 is a potent, orally active PDE10A inhibitor with therapeutic potential in a number of psychiatric indications.
Bioorganic & Medicinal Chemistry Letters | 2015
Douglas F. Burdi; John Emmerson Campbell; Jun Wang; Sufang Zhao; Hua Zhong; Jianfeng Wei; Una Campbell; Liming Shao; Lee W. Herman; Patrick Koch; Philip Jones; Michael Charles Hewitt
The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.
MedChemComm | 2016
Liming Shao; Una Campbell; Q. Kevin Fang; Noel Aaron Powell; John Emmerson Campbell; Philip Jones; Taleen Hanania; Vadim Alexandrov; Irene Morganstern; Emily Sabath; Hua M. Zhong; Thomas H. Large; Kerry L. Spear
Phenotypic drug discovery (PDD) is increasingly being recognized as a viable compliment to target-based drug discovery (TDD). By measuring functional changes, typically at a systems level, PDD can facilitate the identification of compounds having a desirable pharmacology. This capability is particularly important when studying CNS diseases where drug efficacy may require modulation of multiple targets in order to overcome a robust, adaptive biological system. Here, we report the application of a mouse-based high-dimensional behavioral assay to the discovery and optimization of a structurally and mechanistically novel antipsychotic. Lead optimization focused on optimizing complex behavioral features and no explicit effort was made to identify the target (or targets) involved.
Archive | 2013
John Emmerson Campbell; Michael Charles Hewitt; Philip Jones
Archive | 2007
Liming Shao; Fengjiang Wang; Scott Christopher Malcolm; Michael Charles Hewitt; Larry R. Bush; Jianguo Ma; Mark A. Varney; Una Campbell; Sharon Rae Engel; Larry W. Hardy; Patrick Koch; John Emmerson Campbell
Archive | 2010
Liming Shao; John Emmerson Campbell; Michael Charles Hewitt; Una Campbell; Taleen G. Hanania
Archive | 2013
John Emmerson Campbell; Philip Jones
Archive | 2012
John Emmerson Campbell; Philip Jones; Michael Charles Hewitt
Archive | 2011
John Emmerson Campbell; Michael Charles Hewitt; Philip Jones; Linghong Xie