Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacti... more Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX1R and OX2R). In addition to other biological functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX2R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea, which is bound by the OX2R with a pKi of 8.3, has a pKb of 7.9, and is 600-fold selective for the OX2R over the OX1R.A series of novel, selective orexin receptor 2 antagonists consisting of substituted 4-phenyl-[1,3]dioxanes is reported (e.g. 9).
High throughput screening, using the recombinant human H 3 receptor, was used to identify novel h... more High throughput screening, using the recombinant human H 3 receptor, was used to identify novel histamine H 3 receptor antagonists. Evaluation of the lead compounds ultimately afforded potent, selective, orally bioavailable compounds (e.g., 38) with favorable blood-brain barrier penetration. #
We describe the synthesis of a novel class of brain penetrating P2X7 antagonists with high potenc... more We describe the synthesis of a novel class of brain penetrating P2X7 antagonists with high potency at both the rat and human P2X7 receptors. Disclosed herein are druglike molecules with demonstrated target engagement of the rat P2X7 receptors after an oral dose. Specifically, compound 20 occupied the P2X7 receptors >80% over the 6 h time course as measured by an ex vivo radioligand binding experiment. In a dose-response assay, this molecule has a plasma EC50 of 8 ng/mL. Overall, 20 has suitable druglike properties and pharmacokinetics in rat and dog. This molecule and others disclosed herein will serve as additional tools to elucidate the role of the P2X7 receptor in neuropsychiatric disorders.
The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]t... more The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50=7.7nM) and 7u (P2X7 IC50=7.7nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.
Journal of Pharmacology and Experimental Therapeutics, 2003
The in vitro pharmacological properties of N-(1-Acetyl-2,3dihydro-1H-indol-6-yl)-3-(3-cyano-pheny... more The in vitro pharmacological properties of N-(1-Acetyl-2,3dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4yl]-acrylamide (JNJ-5207787), a novel neuropeptide Y Y 2 receptor (Y 2 ) antagonist, were evaluated. JNJ-5207787 inhibited the binding of peptide YY (PYY) to human Y 2 receptor in KAN-Ts cells (pIC 50 ϭ 7.00 Ϯ 0.10) and to rat Y 2 receptors in rat hippocampus (pIC 50 ϭ 7.10 Ϯ 0.20). The compound was Ͼ100-fold selective versus human Y 1 , Y 4 , and Y 5 receptors as evaluated by radioligand binding. In vitro receptor autoradiography data in rat brain tissue sections confirmed the selectivity of JNJ-5207787. [ 125 I]PYY binding sites sensitive to JNJ-5207787 were found in rat brain regions known to express Y 2 receptor (septum, hypothalamus, hippocampus, substantia nigra, and cerebellum), whereas insensitive binding sites were observed in regions known to express Y 1 receptor (cortex and thalamus).
[reaction: see text] A general protocol for the palladium-mediated Suzuki coupling reaction of py... more [reaction: see text] A general protocol for the palladium-mediated Suzuki coupling reaction of pyrazole triflates and aryl boronic acids has been developed. The use of additional dppf ligand was determined to increase product yields allowing for the use of a broad range of reaction substrates.
A series of small molecules based on a chemotype identified from our compound collection were syn... more A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC 50 ) at the human Neuropeptide Y Y 2 receptor (NPY Y 2 ). Six of the 23 analogs tested possessed an NPY Y 2 IC 50 6 15 nM. One member of this series, JNJ 31020028, is a selective, high affinity, receptor antagonist existing as a racemic mixture. As such a synthetic route to the desired enantiomer was designed starting from commercially available (S)-(+)-mandelic acid.
Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacti... more Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX1R and OX2R). In addition to other biological functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX2R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea, which is bound by the OX2R with a pKi of 8.3, has a pKb of 7.9, and is 600-fold selective for the OX2R over the OX1R.A series of novel, selective orexin receptor 2 antagonists consisting of substituted 4-phenyl-[1,3]dioxanes is reported (e.g. 9).
High throughput screening, using the recombinant human H 3 receptor, was used to identify novel h... more High throughput screening, using the recombinant human H 3 receptor, was used to identify novel histamine H 3 receptor antagonists. Evaluation of the lead compounds ultimately afforded potent, selective, orally bioavailable compounds (e.g., 38) with favorable blood-brain barrier penetration. #
We describe the synthesis of a novel class of brain penetrating P2X7 antagonists with high potenc... more We describe the synthesis of a novel class of brain penetrating P2X7 antagonists with high potency at both the rat and human P2X7 receptors. Disclosed herein are druglike molecules with demonstrated target engagement of the rat P2X7 receptors after an oral dose. Specifically, compound 20 occupied the P2X7 receptors >80% over the 6 h time course as measured by an ex vivo radioligand binding experiment. In a dose-response assay, this molecule has a plasma EC50 of 8 ng/mL. Overall, 20 has suitable druglike properties and pharmacokinetics in rat and dog. This molecule and others disclosed herein will serve as additional tools to elucidate the role of the P2X7 receptor in neuropsychiatric disorders.
The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]t... more The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50=7.7nM) and 7u (P2X7 IC50=7.7nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.
Journal of Pharmacology and Experimental Therapeutics, 2003
The in vitro pharmacological properties of N-(1-Acetyl-2,3dihydro-1H-indol-6-yl)-3-(3-cyano-pheny... more The in vitro pharmacological properties of N-(1-Acetyl-2,3dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4yl]-acrylamide (JNJ-5207787), a novel neuropeptide Y Y 2 receptor (Y 2 ) antagonist, were evaluated. JNJ-5207787 inhibited the binding of peptide YY (PYY) to human Y 2 receptor in KAN-Ts cells (pIC 50 ϭ 7.00 Ϯ 0.10) and to rat Y 2 receptors in rat hippocampus (pIC 50 ϭ 7.10 Ϯ 0.20). The compound was Ͼ100-fold selective versus human Y 1 , Y 4 , and Y 5 receptors as evaluated by radioligand binding. In vitro receptor autoradiography data in rat brain tissue sections confirmed the selectivity of JNJ-5207787. [ 125 I]PYY binding sites sensitive to JNJ-5207787 were found in rat brain regions known to express Y 2 receptor (septum, hypothalamus, hippocampus, substantia nigra, and cerebellum), whereas insensitive binding sites were observed in regions known to express Y 1 receptor (cortex and thalamus).
[reaction: see text] A general protocol for the palladium-mediated Suzuki coupling reaction of py... more [reaction: see text] A general protocol for the palladium-mediated Suzuki coupling reaction of pyrazole triflates and aryl boronic acids has been developed. The use of additional dppf ligand was determined to increase product yields allowing for the use of a broad range of reaction substrates.
A series of small molecules based on a chemotype identified from our compound collection were syn... more A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC 50 ) at the human Neuropeptide Y Y 2 receptor (NPY Y 2 ). Six of the 23 analogs tested possessed an NPY Y 2 IC 50 6 15 nM. One member of this series, JNJ 31020028, is a selective, high affinity, receptor antagonist existing as a racemic mixture. As such a synthetic route to the desired enantiomer was designed starting from commercially available (S)-(+)-mandelic acid.
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Papers by Dale Rudolph