Pyridazinoquinolinetriones as NMDA Glycine-Site Antagonists with Oral Antinociceptive Activity in a Model of Neuropathic Pain

Bare, Thomas M.; Brown, Dean G.; Horchler, Carey L.; Murphy, Megan; Urbanek, Rebecca A.; Alford, Vernon; Barlaam, Christine; Dyroff, Martin C.; Empfield, James R.; Forst, Janet M.; Herzog, Keith J.; Keith, Richard A.; Kirschner, Alan S.; Lee, Chi-Ming C.; Lewis, Joseph J.; McLaren, Frances M.; Neilson, K.L.; Steelman, Gary B.; Trivedi, Shephali; Vacek, Edward P.; Xiao, Wen

doi:10.1021/jm060212s

Cited by 13 publications

(5 citation statements)

References 42 publications

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“…1 H-NMR (DMSO- d 6 , 400 MHz) δ: 10.14 (s, 1H), 8.43 (s, 1H), 8.09–8.12 (m, 2H), 7.56–7.60 (m, 1H), 7.48–7.52 (m, 1H). The 1 H-NMR data were in good agreement with those reported [ 54 ].…”

Section: Methodssupporting

confidence: 90%

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

Cai

Liu

et al. 2018

Molecules

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In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a–1x and 1ha–1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 μM against human URAT1 for 1h vs. 7.18 μM and 0.28 μM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.

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Section: Methodssupporting

confidence: 90%

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

Cai

Liu

et al. 2018

Molecules

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“…Another glycine-site NMDAR antagonist, GV196771, also appears to be effective in the animal model of sciatic nerve injury [105,106]. Pyridazinoquinolinetriones are new glycine-site NMDAR antagonists with better aqueous solubility and oral bioavailability, and they can reduce neuropathic pain induced by sciatic nerve injury in rats [107]. …”

Section: Effects Of Nmdar Antagonists In Animal Models Of Neuropathicmentioning

confidence: 99%

TargetingN-methyl-D-aspartate receptors for treatment of neuropathic pain

Zhou

Chen

Pan

2011

Expert Review of Clinical Pharmacology

174

118

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Neuropathic pain remains a major clinical problem and a therapeutic challenge because existing analgesics are often ineffective and can cause serious side effects. Increased N-methyl-D-aspartate receptor (NMDAR) activity contributes to central sensitization in certain types of neuropathic pain. NMDAR antagonists can reduce hyperalgesia and allodynia in animal models of neuropathic pain induced by nerve injury and diabetic neuropathy. Clinically used NMDAR antagonists, such as ketamine and dextromethorphan, are generally effective in patients with neuropathic pain, such as complex regional pain syndrome and painful diabetic neuropathy. However, patients with postherpetic neuralgia respond poorly to NMDAR antagonists. Recent studies on identifying NMDAR-interacting proteins and molecular mechanisms of increased NMDAR activity in neuropathic pain could facilitate the development of new drugs to attenuate abnormal NMDAR activity with minimal impairment of the physiological function of NMDARs. Combining NMDAR antagonists with other analgesics could also lead to better management of neuropathic pain without causing serious side effects.

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“…In particular, glycine has been shown to be a mandatory coagonist necessary for the opening of NMDA receptor ion channels. , The glycine recognition site, located on the NR1 subunit of the NMDA receptor complex, can be distinguished from the inhibitory glycine receptor by its insensitivity to strychnine. It has attracted considerable interest as a potential drug target, as an alternative to the NMDA recognition site itself. ,, A great number of glycine site antagonists from different structural classes have been described in recent years. − However, serious side effects (e.g., memory impairment, neurotoxic or psychotomimetic effects) have been observed with the use of competitive or channel blocking NMDA receptor antagonists in animal models and/or in human clinical trials . Since glycine is an obligatory coagonist, one would expect the same to happen from an antagonist blocking the glycine site.…”

Section: Introductionmentioning

confidence: 99%

“…1,4,5 A great number of glycine site antagonists from different structural classes have been described in recent years. [6][7][8][9][10][11][12][13][14][15][16][17] However, serious side effects (e.g., memory impairment, neurotoxic or psychotomimetic effects) have been observed with the use of competitive or channel blocking NMDA receptor antagonists in animal models and/or in human clinical trials. 18 Since glycine is an obligatory coagonist, one would expect the same to happen from an antagonist blocking the glycine site.…”

Section: Introductionmentioning

confidence: 99%

Drug Design, in Vitro Pharmacology, and Structure−Activity Relationships of 3-Acylamino-2-aminopropionic Acid Derivatives, a Novel Class of Partial Agonists at the Glycine Site on the N-Methyl-d-aspartate (NMDA) Receptor Complex

2009

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Retaining agonistic activity at the glycine coagonist site of the NMDA receptor in molecules derived from glycine or d-serine has proven to be difficult because in the vicinity of the alpha-amino acid group little substitution is tolerated. We have solved this problem by replacing the hydroxy group of d-serine with an amido group, thus keeping the hydrogen donor function and allowing for further substitution and exploration of the adjacent space. Heterocyclic substitutions resulted in a series of 3-acylamino-2-aminopropionic acid derivatives, with high affinities in a binding assay for the glycine site. In a functional assay assessing the activation of the glycine site, these compounds displayed a wide range of intrinsic efficacies, from antagonism to a high degree of partial agonism. Structure-activity relationships reveal that lipophilic substituents, presumably filling an additional hydrophobic pocket, are accepted by the glycine site, provided that they are separated from the alpha-amino acid group by a short linker.

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Pyridazinoquinolinetriones as NMDA Glycine-Site Antagonists with Oral Antinociceptive Activity in a Model of Neuropathic Pain

Cited by 13 publications

References 42 publications

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

TargetingN-methyl-D-aspartate receptors for treatment of neuropathic pain

Drug Design, in Vitro Pharmacology, and Structure−Activity Relationships of 3-Acylamino-2-aminopropionic Acid Derivatives, a Novel Class of Partial Agonists at the Glycine Site on the N-Methyl-d-aspartate (NMDA) Receptor Complex

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