Structure–activity study of l-amino acid-based N-type calcium channel blockers

Seko, Takuya; Kato, Masashi; Kohno, Hiroshi; Ono, Shota; Hashimura, Kazuya; Takimizu, Hideyuki; Nakai, Katsuhiko; Maegawa, Hitoshi; Katsube, Nobuo; Toda, Masaaki

doi:10.1016/s0968-0896(02)00558-8

Cited by 9 publications

(11 citation statements)

References 18 publications

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“…The recent scientific and patent literature has reported a wide range of uncharged compounds effective as N-type calcium channel blockers (Abbadie et al, 2010; Pajouhesh et al, 2012; Patel et al, 2015; Seko et al, 2002; Seko et al, 2003; Shao et al, 2012; Yamamoto and Takahara, 2009; Zamponi et al, 2009), and many of these have structures that can be modified into cationic versions. Our results suggest that making cationic versions of such molecules that have external blocking activity on calcium and sodium channels may be an unexpected new route to identifying new powerful agents well-suited for both treating pain from injury and surgery and inflammatory conditions with a neurogenic component.…”

Section: Discussionmentioning

confidence: 99%

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Lee

Talbot

et al. 2019

eLife

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Voltage-dependent sodium and calcium channels in pain-initiating nociceptor neurons are attractive targets for new analgesics. We made a permanently charged cationic derivative of an N-type calcium channel-inhibitor. Unlike cationic derivatives of local anesthetic sodium channel blockers like QX-314, this cationic compound inhibited N-type calcium channels more effectively with extracellular than intracellular application. Surprisingly, the compound is also a highly effective sodium channel inhibitor when applied extracellularly, producing more potent inhibition than lidocaine or bupivacaine. The charged inhibitor produced potent and long-lasting analgesia in mouse models of incisional wound and inflammatory pain, inhibited release of the neuropeptide calcitonin gene-related peptide (CGRP) from dorsal root ganglion neurons, and reduced inflammation in a mouse model of allergic asthma, which has a strong neurogenic component. The results show that some cationic molecules applied extracellularly can powerfully inhibit both sodium channels and calcium channels, thereby blocking both nociceptor excitability and pro-inflammatory peptide release.

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Section: Discussionmentioning

confidence: 99%

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Lee

Talbot

et al. 2019

eLife

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“…This afforded the HCl salt of 53 as an off-white powdery solid (146 mg, 74%). 1 2-((4′-Chlorobiphenyl-2-yl)methyl)-N-(4-methylbenzyl)-1,2,3,4tetrahydro-isoquinoline-6-carboxamide (54). The procedure used to prepare compound 33 was followed using compound 53 (99 mg, 0.26 mmol), DIEA (183 μL, 1.05 mmol), and 4-methylbenzylamine (67 μL, 0.52 mmol).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Compound 21 was prepared according to a literature procedure. 54 Briefly, to a stirred solution of L-cysteine (20, 200 mg, 1.65 mmol) in a 1:1 solution of NaOH (2 N) and EtOH (total 3.4 mL) was added (bromomethyl)cyclohexane (0.253 mL, 1.82 mmol) followed by tetrabutylammonium iodide (TBAI) (18 mg, 3 mol %). The reaction was allowed to proceed for 3 days at room temperature; then, di-tert-butyl dicarbonate (0.417 mL, 1.82 mmol) was added and the reaction was stirred for a further 24 h at room temperature.…”

Section: Synthesis Of Compound (11) (R)-2-(3-([11′-biphenyl]-4-carbon...mentioning

confidence: 99%

“…Spectral data obtained corresponded to those reported in the literature. 54 (R)-2-((tert-Butoxycarbonyl)amino)-3-((cyclohexylmethyl)sulfonyl)propanoic Acid (22). To a stirred solution of compound 21 (314 mg, 0.99 mmol) in CH 2 Cl 2 (10 mL) at 0 °C was added m-CPBA (max 77%, 444 mg, approx.…”

Section: Synthesis Of Compound (11) (R)-2-(3-([11′-biphenyl]-4-carbon...mentioning

confidence: 99%

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Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-X_L and BCL-2

et al. 2021

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The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-X L , and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein−protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-X L , new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-X L /BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exploration of a cryptic "p5" pocket identified in BCL-X L . This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-X L . Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-X L and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC 50 )) and displaying mechanism-based killing in cells engineered to depend on BCL-X L for survival.

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“…2A ). Oral administration of this compound (30mg/kg) showed analgesic effects in the rat formalin test and CCI neuropathic pain, but high dose (100mg/kg) did not have an effect on cardiac or motor function [126, 127]. …”

Section: Vgcc Inhibitorsmentioning

confidence: 99%

Pharmacological Inhibition of Voltage-gated Ca<sup>2+</sup> Channels for Chronic Pain Relief

Lee¹

2013

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Chronic pain is a major therapeutic problem as the current treatment options are unsatisfactory with low efficacy and deleterious side effects. Voltage-gated Ca2+ channels (VGCCs), which are multi-complex proteins consisting of α1, β, γ, and α2δ subunits, play an important role in pain signaling. These channels are involved in neurogenic inflammation, excitability, and neurotransmitter release in nociceptors. It has been previously shown that N-type VGCCs (Cav2.2) are a major pain target. U.S. FDA approval of three Cav2.2 antagonists, gabapentin, pregabalin, and ziconotide, for chronic pain underlies the importance of this channel subtype. Also, there has been increasing evidence that L-type (Cav1.2) or T-type (Cav3.2) VGCCs may be involved in pain signaling and chronic pain. In order to develop novel pain therapeutics and to understand the role of VGCC subtypes, discovering subtype selective VGCC inhibitors or methods that selectively target the inhibitor into nociceptors would be essential. This review describes the various VGCC subtype inhibitors and the potential of utilizing VGCC subtypes as targets of chronic pain. Development of VGCC subtype inhibitors and targeting them into nociceptors will contribute to a better understanding of the roles of VGCC subtypes in pain at a spinal level as well as development of a novel class of analgesics for chronic pain.

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Structure–activity study of l-amino acid-based N-type calcium channel blockers

Cited by 9 publications

References 18 publications

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-X_L and BCL-2

Pharmacological Inhibition of Voltage-gated Ca<sup>2+</sup> Channels for Chronic Pain Relief

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Structure–activity study of l-amino acid-based N-type calcium channel blockers

Cited by 9 publications

References 18 publications

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2

Pharmacological Inhibition of Voltage-gated Ca<sup>2+</sup> Channels for Chronic Pain Relief

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Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-X_L and BCL-2