Discovery of orally bioavailable cyclohexanol-based NR2B-selective NMDA receptor antagonists with analgesic activity utilizing a scaffold hopping approach

Anan, Kosuke; Masui, Masao; Hara, Shinichiro; Ohara, Miho; Kume, Masaharu; Yamamoto, Shoichi; Shinohara, Shunji; Tsuji, Hiroki; Shimada, Shinji; Yagi, Shigenori; Hasebe, Nobuyoshi; Kai, Hiroyuki

doi:10.1016/j.bmcl.2017.06.076

Cited by 11 publications

(3 citation statements)

References 18 publications

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“…Despite the fact that the oxidative cycloaddition of aldoximes with nitriles has not been described until recently, the method has already found application in medicinal chemistry. Anan and colleagues obtained orally bioavailable cyclohexanol-based NR2B-selective NMDA receptor antagonists with analgesic activity through the oxidative cycloaddition in a low yield with chloramine T as an oxidant ( Scheme 29 ) [ 133 ].…”

Section: Oxidative Cyclizationmentioning

confidence: 99%

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

Baykov

Shetnev

Semenov

et al. 2023

IJMS

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1,2,4-Oxadiazole is an essential motif in drug discovery represented in many experimental, investigational, and marketed drugs. This review covers synthetic methods that allow the conversion of different types of organic compounds into 1,2,4-oxadiazole at ambient temperature and the practical application of the latter approaches for the preparation of pharmaceutically important molecules. The discussed methods are divided into three groups. The first combines two-stage protocols requiring the preliminary preparation of O-acylamidoximes followed by cyclization under the action of organic bases. The advantages of this route are its swiftness, high efficiency of the cyclization process, and uncomplicated work--up. However, it requires the preparation and isolation of O-acylamidoximes as a separate preliminary step. The second route is a one-pot synthesis of 1,2,4-oxadiazoles directly from amidoximes and various carboxyl derivatives or aldehydes in aprotic bipolar solvents (primarily DMSO) in the presence of inorganic bases. This recently proposed pathway proved to be highly efficient in the field of medicinal chemistry. The third group of methods consists of diverse oxidative cyclizations, and these reactions have found modest application in drug design thus far. It is noteworthy that the reviewed methods allow for obtaining 1,2,4-oxadiazoles with thermosensitive functions and expand the prospects of using the oxadiazole core as an amide- or ester-like linker in the design of bioactive compounds.

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Section: Oxidative Cyclizationmentioning

confidence: 99%

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

Baykov

Shetnev

Semenov

et al. 2023

IJMS

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“…GluN2B/NMDAR is an effective target for chronic pain due to its involvement in the disease and distribution in CNS [ 107 ]. Anan and co-workers identified cyclohexanol-based compounds ( 73 ; IC 50 = 7.0 nM and 74 ; IC 50 = 7.1 nM) as selective GluN2B/NMDAR antagonists (Fig.…”

Section: Recent Progress In the Development Of Glun2b Selective Ligandsmentioning

confidence: 99%

GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics

Ugale

Deshmukh

Lokwani³

et al. 2023

Mol Divers

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N -methyl- D -aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brain damage, and neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis. Although a large amount of information is growing consistently on the importance of GluN2B subunit, however, limited recent data is available on how subunit-selective ligands impact NMDAR functions, which blunts the ability to render the diagnosis or craft novel treatments tailored to patients. To bridge this gap, we have focused on and summarized recently reported GluN2B selective ligands as emerging subunit-selective antagonists and modulators of NMDAR. Herein, we have also presented an overview of the structure–function relationship for potential GluN2B/NMDAR ligands with their binding sites and connection to CNS functionalities. Understanding of design rules and roles of GluN2B selective compounds will provide the link to medicinal chemists and neuroscientists to explore novel neurotherapeutic strategies against dysfunctions of glutamatergic neurotransmission. Graphical abstract

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“…Scaffold hopping plays significant roles in lead compounds discovery and optimization in both pharmaceuticals and agrichemicals. [13] The modes of scaffold hopping are various, such as heterocycle mimicking amide, [14] heterocycle replacing another heterocycle, [15,16] ring opening or closing strategy. [17] The ring closing scaffold hopping strategy has been widely applied in insecticides design.…”

Section: Introductionmentioning

confidence: 99%

4‐Oxo‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐d]pyrimidine Derivatives: Design, Synthesis, Insecticidal Assay and Binding Mode Studies

Xiao

Shi

et al. 2022

Chemistry & Biodiversity

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A series of 4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized based on the fipronil low energy conformation by scaffold hopping strategy. Physicochemical properties calculation, insecticidal assay and binding mode studies were also performed. It was found that the target compounds displayed lower insecticidal activities than fipronil. The differences in binding modes between these compounds and fipronil may be the major reason for reduced insecticidal activities.

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Discovery of orally bioavailable cyclohexanol-based NR2B-selective NMDA receptor antagonists with analgesic activity utilizing a scaffold hopping approach

Cited by 11 publications

References 18 publications

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics

4‐Oxo‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐d]pyrimidine Derivatives: Design, Synthesis, Insecticidal Assay and Binding Mode Studies

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