Patent Highlight pubs.acs.org/acsmedchemlett
Modulating GluN2B for the Treatment of Neurological and Psychiatric Disorders Robert B. Kargbo* AMRI, Albany, New York 12212-5098, United States Title:
Modulating GluN2B for the Treatment of Neurological and Psychiatric Disorders
Patent/Patent Application Number:
WO2017007938
Publication date:
January 12, 2017
Priority Application:
US62/190,416
Priority date:
July 9, 2015
Inventors:
Chrovian, C. C.; Letavic, M. A.; Rech, J. C.; Soyode-Johnson, A.; Wall, J. L.
Assignee Company:
Janssen Pharmaceutica and Chrovian, C. C.
Disease Area:
Neurological and psychiatric disorders
Summary:
The N-methyl-D-aspartate receptors (NMDA) are a group of glutamate receptors and ion channel protein found in mammalian species. Cloning of NMDA receptor subunits leads to seven proteins, which are classified into three subunits: GluN1, GluN2, and GluN3. There are two obligatory GluN1 receptors (with a glycine binding site) and two variable GluN2 receptors (with a glutamate binding site), which are encoded by GRIN1 and one of four GRIN2 genes, respectively. In generally, the GluNR2 subunits expressed in different areas of the brain play a dominant role in the functional and pharmacological properties of the NMDA receptors. Furthermore, the GluN2B subunits mainly expressed in the forebrain have been implicated in the regulation of learning, memory processing, mood attention, emotion, and pain perception.
Biological Target:
NR2B Receptor
NMDA receptors are different from other major subtypes of glutamate receptor since they are blocked by Mg2+ at membrane potentials, are highly Ca2+ permeable, and require glutamate and glycine neurotransmitters as coactivators. An increase in the levels of NMDA receptor within the brain may cause memory and learning impairments. Consequently, compounds that modulate GluN2B-containing NMDA receptors may be useful in the treatment of many neurological and psychiatric disorders. The present disclosure describes compounds capable of modulating GluN2B receptors that are useful in the treatment of diseases such as Alzheimer’s, Parkinson’s, bipolar disorder, additive illnesses, autism, migraine, and treatment-resistant depression. Important Compound Classes:
Key Structures:
The inventors described synthetic procedures and listed structures of 639 compounds of Formulas I, II, and IIA, including the following representative examples:
Received: July 30, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00309 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Recent Review Articles:
Patent Highlight
1. Goff, D. C. Current Neuropharmacology 2017, 15 (1), 21−34. 2. Tovar, K. R.; Westbrook, G. L. Neuropharmacology 2017, 112 (Part A), 29−33. 3. Hu, C.; Chen, W.; Myers, S. J.; Yuan, H.; Traynelis, S. F. Journal of Pharmacological Sciences 2016, 132 (2), 115−121. 4. Wang, M.; Arnsten, A. F. T. Neuroscience Bulletin 2015, 31 (2), 191−197. 5. Korczyn, A. D.; Zadori, D.; Veres, G.; Szalardy, L.; Klivenyi, P.; Toldi, J.; Vecsei, L. Journal of Alzheimer’s Disease 2014, 42 (Suppl. 3), S177−S187.
Biological Assay:
The antagonist activity of rat and human NR1/NR2B receptors. The assay depends on the binding ability of a tracer to the GluN2B subunit containing the NMDA receptors and the ability of the test compound to displace the GluN2B-NMDA conjugate. Alternatively, the assay measures the binding affinity for ligands that compete for the ifenprodil binding site in the native NMDA receptors. To measure the function of the NMDA receptor, a cell-based calcium flux assay was carried out. In this assay, glutamate and glycine coagonists are added to cells expressing the human GluN1/GluN2B NMDA receptors, which initiate cellular Ca2+ influx. This causes a change in the calcium influx, which is measured using a fluorescent dye and a fluorometric imaging plate reader (FLIPR) device.
Biological Data:
The biological data obtained from testing the above representative compounds of Formula I are listed in the following table:
Claims:
33 Total claims 27 Composition of matter claims 6 Method of use claims B
DOI: 10.1021/acsmedchemlett.7b00309 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
■
Patent Highlight
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]. Notes
The author declares no competing financial interest.
C
DOI: 10.1021/acsmedchemlett.7b00309 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Modulating GluN2B for the Treatment of Neurological and Psychiatric Disorders Robert B. Kargbo* AMRI, Albany, New York 12212-5098, United States Title:
Modulating GluN2B for the Treatment of Neurological and Psychiatric Disorders
Patent/Patent Application Number:
WO2017007938
Publication date:
January 12, 2017
Priority Application:
US62/190,416
Priority date:
July 9, 2015
Inventors:
Chrovian, C. C.; Letavic, M. A.; Rech, J. C.; Soyode-Johnson, A.; Wall, J. L.
Assignee Company:
Janssen Pharmaceutica and Chrovian, C. C.
Disease Area:
Neurological and psychiatric disorders
Summary:
The N-methyl-D-aspartate receptors (NMDA) are a group of glutamate receptors and ion channel protein found in mammalian species. Cloning of NMDA receptor subunits leads to seven proteins, which are classified into three subunits: GluN1, GluN2, and GluN3. There are two obligatory GluN1 receptors (with a glycine binding site) and two variable GluN2 receptors (with a glutamate binding site), which are encoded by GRIN1 and one of four GRIN2 genes, respectively. In generally, the GluNR2 subunits expressed in different areas of the brain play a dominant role in the functional and pharmacological properties of the NMDA receptors. Furthermore, the GluN2B subunits mainly expressed in the forebrain have been implicated in the regulation of learning, memory processing, mood attention, emotion, and pain perception.
Biological Target:
NR2B Receptor
NMDA receptors are different from other major subtypes of glutamate receptor since they are blocked by Mg2+ at membrane potentials, are highly Ca2+ permeable, and require glutamate and glycine neurotransmitters as coactivators. An increase in the levels of NMDA receptor within the brain may cause memory and learning impairments. Consequently, compounds that modulate GluN2B-containing NMDA receptors may be useful in the treatment of many neurological and psychiatric disorders. The present disclosure describes compounds capable of modulating GluN2B receptors that are useful in the treatment of diseases such as Alzheimer’s, Parkinson’s, bipolar disorder, additive illnesses, autism, migraine, and treatment-resistant depression. Important Compound Classes:
Key Structures:
The inventors described synthetic procedures and listed structures of 639 compounds of Formulas I, II, and IIA, including the following representative examples:
Received: July 30, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00309 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Recent Review Articles:
Patent Highlight
1. Goff, D. C. Current Neuropharmacology 2017, 15 (1), 21−34. 2. Tovar, K. R.; Westbrook, G. L. Neuropharmacology 2017, 112 (Part A), 29−33. 3. Hu, C.; Chen, W.; Myers, S. J.; Yuan, H.; Traynelis, S. F. Journal of Pharmacological Sciences 2016, 132 (2), 115−121. 4. Wang, M.; Arnsten, A. F. T. Neuroscience Bulletin 2015, 31 (2), 191−197. 5. Korczyn, A. D.; Zadori, D.; Veres, G.; Szalardy, L.; Klivenyi, P.; Toldi, J.; Vecsei, L. Journal of Alzheimer’s Disease 2014, 42 (Suppl. 3), S177−S187.
Biological Assay:
The antagonist activity of rat and human NR1/NR2B receptors. The assay depends on the binding ability of a tracer to the GluN2B subunit containing the NMDA receptors and the ability of the test compound to displace the GluN2B-NMDA conjugate. Alternatively, the assay measures the binding affinity for ligands that compete for the ifenprodil binding site in the native NMDA receptors. To measure the function of the NMDA receptor, a cell-based calcium flux assay was carried out. In this assay, glutamate and glycine coagonists are added to cells expressing the human GluN1/GluN2B NMDA receptors, which initiate cellular Ca2+ influx. This causes a change in the calcium influx, which is measured using a fluorescent dye and a fluorometric imaging plate reader (FLIPR) device.
Biological Data:
The biological data obtained from testing the above representative compounds of Formula I are listed in the following table:
Claims:
33 Total claims 27 Composition of matter claims 6 Method of use claims B
DOI: 10.1021/acsmedchemlett.7b00309 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
■
Patent Highlight
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]. Notes
The author declares no competing financial interest.
C
DOI: 10.1021/acsmedchemlett.7b00309 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
