Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Review of Voltage-gated Calcium Channel α2δ Subunit Ligands for the Treatment of Chronic Neuropathic Pain and Insight into Structure-activity Relationship (SAR) by Pharmacophore Modeling

Author(s): Yuting Chen, Qingqing Wu, Zhengsheng Jin, Yanlan Qin, Fancui Meng* and Guilong Zhao*

Volume 29, Issue 30, 2022

Published on: 15 June, 2022

Page: [5097 - 5112] Pages: 16

DOI: 10.2174/0929867329666220407093727

Price: $65

Abstract

Background: Neuropathic pain (NP) is a complex symptom related to nerve damage. The discovery of new drugs for treating chronic NP has been continuing for several decades, while more progress is still needed because of the unsatisfactory efficacy and the side effects of the currently available drugs. Among all the approved drugs for chronic NP, voltage- gated calcium channel (VGCC) α2δ subunit ligands, also known as gabapentinoids, are among the first-line treatment and represent a class of efficacious and relatively safe therapeutic agents. However, new strategies are still needed to be explored due to the unsatisfied response rate.

Objective: The aim of the study is to review the latest status of the discovery and development of gabapentinoids for the treatment of chronic NP by covering both the marketed and the preclinical/clinical ones. Moreover, it aims to analyze the structure-activity relationship (SAR) of gabapentinoids to facilitate the future design of structurally novel therapeutic agents targeting the VGCC α2δ subunit.

Methods: We searched PubMed Central, Embase, Cochrane Library, Web of Science, Scopus, and Espacenet for the literature and patents on diabetic peripheral neuropathic pain, postherpetic neuralgia, fibromyalgia, voltage-gated calcium channel α2δ subunit and related therapeutic agents from incipient to June 10, 2021. The SAR of gabapentinoids was analyzed by pharmacophore modeling using the Phase module in the Schrödinger suite.

Results: A variety of gabapentinoids were identified as VGCC α2δ ligands that have ever been under development to treat chronic NP. Among them, four gabapentinoids are marketed, one is in the active late clinical trials, and eight have been discontinued. Pharmacophore models were generated using the phase module in the Schrödinger suite, and common pharmacophores were predicted based on pharmacophoric features and analyzed.

Conclusion: The latest progress in the discovery and development of gabapentinoids for the treatment of chronic NP was reviewed. Moreover, the structure-activity relationship (SAR) of gabapentinoids has been analyzed by pharmacophore modeling, which will be valuable for the future design of structurally novel therapeutic agents targeting the VGCC α2δ subunit.

Keywords: Voltage-gated calcium channel, α2δ subunit, neuropathic pain, structure-activity relationship (SAR), pharmacophore modeling, gabapentinoids.

« Previous Next »
[1]
Gilron, I.; Baron, R.; Jensen, T. Neuropathic pain: Principles of diagnosis and treatment. Mayo Clin. Proc., 2015, 90(4), 532-545.
[http://dx.doi.org/10.1016/j.mayocp.2015.01.018] [PMID: 25841257]
[2]
Lauria, G.; Ziegler, D.; Malik, R.; Merkies, I.S.; Waxman, S.G.; Faber, C.G.; Group, P.S. The role of sodium channels in painful diabetic and idiopathic neuropathy. Curr. Diab. Rep., 2014, 14(10), 538.
[http://dx.doi.org/10.1007/s11892-014-0538-5] [PMID: 25142720]
[3]
Murnion, B.P. Neuropathic pain: Current definition and review of drug treatment. Aust. Prescr., 2018, 41(3), 60-63.
[http://dx.doi.org/10.18773/austprescr.2018.022] [PMID: 29921999]
[4]
Cherif, F.; Zouari, H.G.; Cherif, W.; Hadded, M.; Cheour, M.; Damak, R. Depression prevalence in neuropathic pain and its impact on the quality of life. Pain Res. Manag., 2020, 2020, 7408508.
[http://dx.doi.org/10.1155/2020/7408508] [PMID: 32617124]
[5]
Deeks, E.D. Mirogabalin: First global approval. Drugs, 2019, 79(4), 463-468.
[http://dx.doi.org/10.1007/s40265-019-01070-8] [PMID: 30778848]
[6]
Snedecor, S.J.; Sudharshan, L.; Cappelleri, J.C.; Sadosky, A.; Desai, P.; Jalundhwala, Y.J.; Botteman, M. Systematic review and comparison of pharmacologic therapies for neuropathic pain associated with spinal cord injury. J. Pain Res., 2013, 6, 539-547.
[http://dx.doi.org/10.2147/JPR.S45966] [PMID: 23874121]
[7]
Butera, J.A. Current and emerging targets to treat neuropathic pain. J. Med. Chem., 2007, 50(11), 2543-2546.
[http://dx.doi.org/10.1021/jm061015w] [PMID: 17489576]
[8]
DiBonaventura, M.D.; Sadosky, A.; Concialdi, K.; Hopps, M.; Kudel, I.; Parsons, B.; Cappelleri, J.C.; Hlavacek, P.; Alexander, A.H.; Stacey, B.R.; Markman, J.D.; Farrar, J.T. The prevalence of probable neuropathic pain in the US: Results from a multimodal general-population health survey. J. Pain Res., 2017, 10, 2525-2538.
[http://dx.doi.org/10.2147/JPR.S127014] [PMID: 29138590]
[9]
Yawn, B.P.; Wollan, P.C.; Weingarten, T.N.; Watson, J.C.; Hooten, W.M.; Melton, L.J., III The prevalence of neuropathic pain: Clinical evaluation compared with screening tools in a community population. Pain Med., 2009, 10(3), 586-593.
[http://dx.doi.org/10.1111/j.1526-4637.2009.00588.x] [PMID: 20849570]
[10]
Gylfadottir, S.S.; Christensen, D.H.; Nicolaisen, S.K.; Andersen, H.; Callaghan, B.C.; Itani, M.; Khan, K.S.; Kristensen, A.G.; Nielsen, J.S.; Sindrup, S.H.; Andersen, N.T.; Jensen, T.S.; Thomsen, R.W.; Finnerup, N.B. Diabetic polyneuropathy and pain, prevalence, and patient characteristics: A cross-sectional questionnaire study of 5,514 patients with recently diagnosed type 2 diabetes. Pain, 2020, 161(3), 574-583.
[http://dx.doi.org/10.1097/j.pain.0000000000001744] [PMID: 31693539]
[11]
Yu, S.Y.; Fan, B.F.; Yang, F.; DiBonaventura, M.; Chen, Y.X.; Li, R.Y.; King-Concialdi, K.; Kudel, I.; Hlavacek, P.; Hopps, M.; Udall, M.; Sadosky, A.; Cappelleri, J.C. Patient and economic burdens of postherpetic neuralgia in China. Clinicoecon. Outcomes Res., 2019, 11, 539-550.
[http://dx.doi.org/10.2147/CEOR.S203920] [PMID: 31564930]
[12]
Yang, F.; Yu, S.; Fan, B.; Liu, Y.; Chen, Y.X.; Kudel, I.; Concialdi, K.; DiBonaventura, M.; Hopps, M.; Hlavacek, P.; Cappelleri, J.C.; Sadosky, A.; Parsons, B.; Udall, M. The epidemiology of herpes zoster and postherpetic neuralgia in China: Results from a cross-sectional study. Pain Ther., 2019, 8(2), 249-259.
[http://dx.doi.org/10.1007/s40122-019-0127-z] [PMID: 31218562]
[13]
Lawson, K. Potential drug therapies for the treatment of fibromyalgia. Expert Opin. Investig. Drugs, 2016, 25(9), 1071-1081.
[http://dx.doi.org/10.1080/13543784.2016.1197906] [PMID: 27269389]
[14]
Sadosky, A.; Schaefer, C.; Mann, R.; Bergstrom, F.; Baik, R.; Parsons, B.; Nalamachu, S.; Nieshoff, E.; Stacey, B.R.; Anschel, A.; Tuchman, M. Burden of illness associated with painful diabetic peripheral neuropathy among adults seeking treatment in the US: Results from a retrospective chart review and cross-sectional survey. Diabetes Metab. Syndr. Obes., 2013, 6, 79-92.
[http://dx.doi.org/10.2147/DMSO.S37415] [PMID: 23403729]
[15]
Schaefer, C.; Mann, R.; Sadosky, A.; Daniel, S.; Parsons, B.; Nieshoff, E.; Tuchman, M.; Nalamachu, S.; Anschel, A.; Stacey, B.R. Burden of illness associated with peripheral and central neuropathic pain among adults seeking treatment in the United States: A patient-centered evaluation. Pain Med., 2014, 15(12), 2105-2119.
[http://dx.doi.org/10.1111/pme.12502] [PMID: 25039856]
[16]
Geisler, S.; Schöpf, C.L.; Obermair, G.J. Emerging evidence for specific neuronal functions of auxiliary calcium channel α2δ subunits. Gen. Physiol. Biophys., 2015, 34(2), 105-118.
[http://dx.doi.org/10.4149/gpb_2014037] [PMID: 25504062]
[17]
Dolphin, A.C. Voltage-gated calcium channels and their auxiliary subunits: Physiology and pathophysiology and pharmacology. J. Physiol., 2016, 594(19), 5369-5390.
[http://dx.doi.org/10.1113/JP272262] [PMID: 27273705]
[18]
Xiang, B.; Liu, Y.; Xie, L.; Zhao, Q.; Zhang, L.; Gan, X.; Yu, H. The osteoclasts attach to the bone surface where the extracellular calcium concentration decreases. Cell Biochem. Biophys., 2016, 74(4), 553-558.
[http://dx.doi.org/10.1007/s12013-016-0757-2] [PMID: 27718044]
[19]
Risher, W.C.; Eroglu, C. Emerging roles for α2δ subunits in calcium channel function and synaptic connectivity. Curr. Opin. Neurobiol., 2020, 63, 162-169.
[http://dx.doi.org/10.1016/j.conb.2020.04.007] [PMID: 32521436]
[20]
Davies, A.; Hendrich, J.; Van Minh, A.T.; Wratten, J.; Douglas, L.; Dolphin, A.C. Functional biology of the α(2)δ subunits of voltage-gated calcium channels. Trends Pharmacol. Sci., 2007, 28(5), 220-228.
[http://dx.doi.org/10.1016/j.tips.2007.03.005] [PMID: 17403543]
[21]
Burgess, G.; Williams, D. The discovery and development of analgesics: New mechanisms, new modalities. J. Clin. Invest., 2010, 120(11), 3753-3759.
[http://dx.doi.org/10.1172/JCI43195] [PMID: 21041957]
[22]
Bauer, C.S.; Tran-Van-Minh, A.; Kadurin, I.; Dolphin, A.C. A new look at calcium channel α2δ subunits. Curr. Opin. Neurobiol., 2010, 20(5), 563-571.
[http://dx.doi.org/10.1016/j.conb.2010.05.007] [PMID: 20579869]
[23]
Patel, R.; Bauer, C.S.; Nieto-Rostro, M.; Margas, W.; Ferron, L.; Chaggar, K.; Crews, K.; Ramirez, J.D.; Bennett, D.L.; Schwartz, A.; Dickenson, A.H.; Dolphin, A.C. α2δ-1 gene deletion affects somatosensory neuron function and delays mechanical hypersensitivity in response to peripheral nerve damage. J. Neurosci., 2013, 33(42), 16412-16426.
[http://dx.doi.org/10.1523/JNEUROSCI.1026-13.2013] [PMID: 24133248]
[24]
Zamponi, G.W.; Striessnig, J.; Koschak, A.; Dolphin, A.C. The Physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol. Rev., 2015, 67(4), 821-870.
[http://dx.doi.org/10.1124/pr.114.009654] [PMID: 26362469]
[25]
Fuller-Bicer, G.A.; Varadi, G.; Koch, S.E.; Ishii, M.; Bodi, I.; Kadeer, N.; Muth, J.N.; Mikala, G.; Petrashevskaya, N.N.; Jordan, M.A.; Zhang, S.P.; Qin, N.; Flores, C.M.; Isaacsohn, I.; Varadi, M.; Mori, Y.; Jones, W.K.; Schwartz, A. Targeted disruption of the voltage-dependent calcium channel α2/δ-1-subunit. Am. J. Physiol. Heart Circ. Physiol., 2009, 297(1), H117-H124.
[http://dx.doi.org/10.1152/ajpheart.00122.2009] [PMID: 19429829]
[26]
Dolphin, A.C. Voltage-gated calcium channels: Their discovery, function and importance as drug targets. Brain Neurosci. Adv., 2018, 2, 1-8.
[http://dx.doi.org/10.1177/2398212818794805] [PMID: 30320224]
[27]
Caroleo, M.C.; Brizzi, A.; De Rosa, M.; Pandey, A.; Gallelli, L.; Badolato, M.; Carullo, G.; Cione, E. Targeting neuropathic pain: Pathobiology, current treatment and peptidomimetics as a new therapeutic opportunity. Curr. Med. Chem., 2020, 27(9), 1469-1500.
[http://dx.doi.org/10.2174/0929867326666190530121133] [PMID: 31142248]
[28]
Kremer, M.; Salvat, E.; Muller, A.; Yalcin, I.; Barrot, M. Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights. Neuroscience, 2016, 338, 183-206.
[http://dx.doi.org/10.1016/j.neuroscience.2016.06.057] [PMID: 27401055]
[29]
Fornasari, D. Pharmacotherapy for neuropathic pain: A review. Pain Ther., 2017, 6(S1)(Suppl. 1), 25-33.
[http://dx.doi.org/10.1007/s40122-017-0091-4] [PMID: 29178034]
[30]
Khdour, M.R. Treatment of diabetic peripheral neuropathy: A review. J. Pharm. Pharmacol., 2020, 72(7), 863-872.
[http://dx.doi.org/10.1111/jphp.13241] [PMID: 32067247]
[31]
Stahl, S.M.; Porreca, F.; Taylor, C.P.; Cheung, R.; Thorpe, A.J.; Clair, A. The diverse therapeutic actions of pregabalin: Is a single mechanism responsible for several pharmacological activities? Trends Pharmacol. Sci., 2013, 34(6), 332-339.
[http://dx.doi.org/10.1016/j.tips.2013.04.001] [PMID: 23642658]
[32]
Widerström-Noga, E. Neuropathic pain and spinal cord injury: Phenotypes and pharmacological management. Drugs, 2017, 77(9), 967-984.
[http://dx.doi.org/10.1007/s40265-017-0747-8] [PMID: 28451808]
[33]
Tauben, D. Nonopioid medications for pain. Phys. Med. Rehabil. Clin. N. Am., 2015, 26(2), 219-248.
[http://dx.doi.org/10.1016/j.pmr.2015.01.005] [PMID: 25952062]
[34]
Alam, U.; Sloan, G.; Tesfaye, S. Treating pain in diabetic neuropathy: Current and developmental drugs. Drugs, 2020, 80(4), 363-384.
[http://dx.doi.org/10.1007/s40265-020-01259-2] [PMID: 32040849]
[35]
Chivukula, S.; Tempel, Z.J.; Chen, C.J.; Shin, S.S.; Gande, A.V.; Moossy, J.J. Spinal and nucleus caudalis dorsal root entry zone lesioning for chronic pain: Efficacy and outcomes. World Neurosurg., 2015, 84(2), 494-504.
[http://dx.doi.org/10.1016/j.wneu.2015.04.025] [PMID: 25900792]
[36]
Arnold, L.M. Biology and therapy of fibromyalgia. New therapies in fibromyalgia. Arthritis Res. Ther., 2006, 8(4), 212.
[http://dx.doi.org/10.1186/ar1971] [PMID: 16762044]
[37]
Stemkowski, P.L.; Biggs, J.E.; Chen, Y.; Bukhanova, N.; Kumar, N.; Smith, P.A. Understanding and treating neuropathic pain. Neurophysiology, 2013, 45(1), 67-78.
[http://dx.doi.org/10.1007/s11062-013-9338-9]
[38]
Schaller, D.; Sribar, D.; Noonan, T.; Deng, L.; Nguyen, T.N.; Pach, S.; Machalz, D.; Bermudez, M.; Wolber, G. Next generation 3D pharmacophore modeling. WIREs Comput. Mol. Sci., 2020, 10(4), e1468.
[39]
Chincholkar, M. Gabapentinoids: Pharmacokinetics, pharmacodynamics and considerations for clinical practice. Br. J. Pain, 2020, 14(2), 104-114.
[http://dx.doi.org/10.1177/2049463720912496] [PMID: 32537149]
[40]
İlhanlı, İ.; Güder, N.; Gül, M. Gabapentinoids in penitentiaries: An abuse and addiction research. Turk. J. Phys. Med. Rehabil., 2017, 63(4), 318-328.
[http://dx.doi.org/10.5606/tftrd.2017.651] [PMID: 31453474]
[41]
Oyama, M.; Watanabe, S.; Iwai, T.; Tanabe, M. Mirogabalin activates the descending noradrenergic system by binding to the α2δ-1 subunit of voltage-gated Ca2+ channels to generate analgesic effects. J. Pharmacol. Sci., 2021, 146(1), 33-39.
[http://dx.doi.org/10.1016/j.jphs.2021.01.002] [PMID: 33858653]
[42]
Taylor, C.P. Mechanisms of analgesia by gabapentin and pregabalin--calcium channel α2-δ [Cavalpha2-δ] ligands. Pain, 2009, 142(1-2), 13-16.
[http://dx.doi.org/10.1016/j.pain.2008.11.019] [PMID: 19128880]
[43]
Chincholkar, M. Analgesic mechanisms of gabapentinoids and effects in experimental pain models: A narrative review. Br. J. Anaesth., 2018, 120(6), 1315-1334.
[http://dx.doi.org/10.1016/j.bja.2018.02.066] [PMID: 29793598]
[44]
Bán, E.G.; Brassai, A.; Vizi, E.S. The role of the endogenous neurotransmitters associated with neuropathic pain and in the opioid crisis: The innate pain-relieving system. Brain Res. Bull., 2020, 155, 129-136.
[http://dx.doi.org/10.1016/j.brainresbull.2019.12.001] [PMID: 31816407]
[45]
Kukkar, A.; Bali, A.; Singh, N.; Jaggi, A.S. Implications and mechanism of action of gabapentin in neuropathic pain. Arch. Pharm. Res., 2013, 36(3), 237-251.
[http://dx.doi.org/10.1007/s12272-013-0057-y] [PMID: 23435945]
[46]
Sills, G.J. The mechanisms of action of gabapentin and pregabalin. Curr. Opin. Pharmacol., 2006, 6(1), 108-113.
[http://dx.doi.org/10.1016/j.coph.2005.11.003] [PMID: 16376147]
[47]
Blakemore, D.C.; Bryans, J.S.; Carnell, P.; Chessum, N.E.; Field, M.J.; Kinsella, N.; Kinsora, J.K.; Osborne, S.A.; Williams, S.C. Synthesis and in vivo evaluation of 3-substituted gababutins. Bioorg. Med. Chem. Lett., 2010, 20(1), 362-365.
[http://dx.doi.org/10.1016/j.bmcl.2009.10.089] [PMID: 19897364]
[48]
Beal, B.; Moeller-Bertram, T.; Schilling, J.M.; Wallace, M.S. Gabapentin for once-daily treatment of post-herpetic neuralgia: A review. Clin. Interv. Aging, 2012, 7, 249-255.
[PMID: 22866002]
[49]
Calandre, E.P.; Rico-Villademoros, F.; Slim, M. Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: A review of their clinical pharmacology and therapeutic use. Expert Rev. Neurother., 2016, 16(11), 1263-1277.
[http://dx.doi.org/10.1080/14737175.2016.1202764] [PMID: 27345098]
[50]
Wang, J.; Zhu, Y. Different doses of gabapentin formulations for postherpetic neuralgia: A systematical review and meta-analysis of randomized controlled trials. J. Dermatolog. Treat., 2017, 28(1), 65-77.
[http://dx.doi.org/10.3109/09546634.2016.1163315] [PMID: 27798973]
[51]
Cundy, K.C.; Annamalai, T.; Bu, L.; De Vera, J.; Estrela, J.; Luo, W.; Shirsat, P.; Torneros, A.; Yao, F.; Zou, J.; Barrett, R.W.; Gallop, M.A. XP13512 [(+/-)-1-([(α-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J. Pharmacol. Exp. Ther., 2004, 311(1), 324-333.
[http://dx.doi.org/10.1124/jpet.104.067959] [PMID: 15146029]
[52]
Cundy, K.C.; Branch, R.; Chernov-Rogan, T.; Dias, T.; Estrada, T.; Hold, K.; Koller, K.; Liu, X.; Mann, A.; Panuwat, M.; Raillard, S.P.; Upadhyay, S.; Wu, Q.Q.; Xiang, J.N.; Yan, H.; Zerangue, N.; Zhou, C.X.; Barrett, R.W.; Gallop, M.A. XP13512 [(+/-)-1-([(α-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J. Pharmacol. Exp. Ther., 2004, 311(1), 315-323.
[http://dx.doi.org/10.1124/jpet.104.067934] [PMID: 15146028]
[53]
Cundy, K.C.; Sastry, S.; Luo, W.; Zou, J.; Moors, T.L.; Canafax, D.M. Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin. J. Clin. Pharmacol., 2008, 48(12), 1378-1388.
[http://dx.doi.org/10.1177/0091270008322909] [PMID: 18827074]
[54]
Lal, R.; Sukbuntherng, J.; Luo, W.; Chen, D.; Blumenthal, R.; Ho, J.; Cundy, K.C. Clinical pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study. Clin. Ther., 2012, 34(1), 201-213.
[http://dx.doi.org/10.1016/j.clinthera.2011.12.004] [PMID: 22206794]
[55]
Schifano, F. Misuse and abuse of pregabalin and gabapentin: Cause for concern? CNS Drugs, 2014, 28(6), 491-496.
[http://dx.doi.org/10.1007/s40263-014-0164-4] [PMID: 24760436]
[56]
Dworkin, R.H.; O’Connor, A.B.; Audette, J.; Baron, R.; Gourlay, G.K.; Haanpää, M.L.; Kent, J.L.; Krane, E.J.; Lebel, A.A.; Levy, R.M.; Mackey, S.C.; Mayer, J.; Miaskowski, C.; Raja, S.N.; Rice, A.S.; Schmader, K.E.; Stacey, B.; Stanos, S.; Treede, R.D.; Turk, D.C.; Walco, G.A.; Wells, C.D. Recommendations for the pharmacological management of neuropathic pain: An overview and literature update. Mayo Clin. Proc., 2010, 85(3)(Suppl.), S3-S14.
[http://dx.doi.org/10.4065/mcp.2009.0649] [PMID: 20194146]
[57]
Zajączkowska, R.; Mika, J.; Leppert, W.; Kocot-Kępska, M.; Malec-Milewska, M.; Wordliczek, J. Mirogabalin-a novel selective ligand for the alpha2delta calcium channel subunit. Pharmaceuticals (Basel), 2021, 14(2), 112.
[http://dx.doi.org/10.3390/ph14020112] [PMID: 33572689]
[58]
Domon, Y.; Arakawa, N.; Inoue, T.; Matsuda, F.; Takahashi, M.; Yamamura, N.; Kai, K.; Kitano, Y. Binding characteristics and analgesic effects of mirogabalin, a novel ligand for the α2δ subunit of voltage-gated calcium channels. J. Pharmacol. Exp. Ther., 2018, 365(3), 573-582.
[http://dx.doi.org/10.1124/jpet.117.247551] [PMID: 29563324]
[59]
Baba, M.; Matsui, N.; Kuroha, M.; Wasaki, Y.; Ohwada, S. Long-term safety and efficacy of mirogabalin in Asian patients with diabetic peripheral neuropathic pain. J. Diabetes Investig., 2020, 11(3), 693-698.
[http://dx.doi.org/10.1111/jdi.13178] [PMID: 31722446]
[60]
Kato, J.; Baba, M.; Kuroha, M.; Kakehi, Y.; Murayama, E.; Wasaki, Y.; Ohwada, S. Safety and efficacy of mirogabalin for peripheral neuropathic pain: Pooled analysis of two pivotal phase III studies. Clin. Ther., 2021, 43(5), 822-835.e16.
[http://dx.doi.org/10.1016/j.clinthera.2021.03.015] [PMID: 34059327]
[61]
Domon, Y.; Kitano, Y.; Makino, M. Analgesic effects of the novel α2 δ ligand mirogabalin in a rat model of spinal cord injury. Pharmazie, 2018, 73(11), 659-661.
[PMID: 30396385]
[62]
Hutmacher, M.M.; Frame, B.; Miller, R.; Truitt, K.; Merante, D. Exposure-response modeling of average daily pain score, and dizziness and somnolence, for mirogabalin (DS-5565) in patients with diabetic peripheral neuropathic pain. J. Clin. Pharmacol., 2016, 56(1), 67-77.
[http://dx.doi.org/10.1002/jcph.567] [PMID: 26073181]
[63]
Duchin, K.; Senaldi, G.; Warren, V.; Marbury, T.; Lasseter, K.; Zahir, H. Open-label single-dose study to assess the effect of mild and moderate hepatic impairment on the pharmacokinetics of mirogabalin. Clin. Drug Investig., 2018, 38(11), 1001-1009.
[http://dx.doi.org/10.1007/s40261-018-0692-7] [PMID: 30171457]
[64]
Baba, M.; Takatsuna, H.; Matsui, N.; Ohwada, S. Mirogabalin in Japanese patients with renal impairment and pain associated with diabetic peripheral neuropathy or post-herpetic neuralgia: A phase III, open-label, 14-week study. J. Pain Res., 2020, 13, 1811-1821.
[http://dx.doi.org/10.2147/JPR.S255345] [PMID: 32765056]
[65]
Gou, X.; Yu, X.; Bai, D.; Tan, B.; Cao, P.; Qian, M.; Zheng, X.; Chen, L.; Shi, Z.; Li, Y.; Ye, F.; Liang, Y.; Ni, J. Pharmacology and mechanism of action of HSK16149, a selective ligand of α2δ subunit of voltage-gated calcium channel with analgesic activity in animal models of chronic pain. J. Pharmacol. Exp. Ther., 2021, 376(3), 330-337.
[http://dx.doi.org/10.1124/jpet.120.000315] [PMID: 33293377]
[66]
Maghani, P.; Kricek, F. Gamma-aminobutyric acid (GABA) analogues for the treatment of pain and other diseases. Patent No. WO2015/091461A1, 2015.
[67]
Schwarz, J.B.; Colbry, N.L.; Zhu, Z.; Nichelson, B.; Barta, N.S.; Lin, K.; Hudack, R.A.; Gibbons, S.E.; Galatsis, P.; DeOrazio, R.J.; Manning, D.D.; Vartanian, M.G.; Kinsora, J.J.; Lotarski, S.M.; Li, Z.; Dickerson, M.R.; El-Kattan, A.; Thorpe, A.J.; Donevan, S.D.; Taylor, C.P.; Wustrow, D.J. Carboxylate bioisosteres of pregabalin. Bioorg. Med. Chem. Lett., 2006, 16(13), 3559-3563.
[http://dx.doi.org/10.1016/j.bmcl.2006.03.083] [PMID: 16621528]
[68]
Nickel, J.C.; Crossland, A.; Davis, E.; Haab, F.; Mills, I.W.; Rovner, E.; Scholfield, D.; Crook, T. Investigation of a Ca2+ channel α2δ ligand for the treatment of interstitial cystitis: Results of a randomized, double-blind, placebo controlled phase II trial. J. Urol., 2012, 188(3), 817-823.
[http://dx.doi.org/10.1016/j.juro.2012.05.010] [PMID: 22818144]
[69]
Chuang, Y.C.; Chermansky, C.; Kashyap, M.; Tyagi, P. Investigational drugs for bladder pain syndrome (BPS) / interstitial cystitis (IC). Expert Opin. Investig. Drugs, 2016, 25(5), 521-529.
[http://dx.doi.org/10.1517/13543784.2016.1162290] [PMID: 26940379]
[70]
Blakemore, D.C.; Bryans, J.S.; Carnell, P.; Carr, C.L.; Chessum, N.E.; Field, M.J.; Kinsella, N.; Osborne, S.A.; Warren, A.N.; Williams, S.C. Synthesis and in vivo evaluation of bicyclic gababutins. Bioorg. Med. Chem. Lett., 2010, 20(2), 461-464.
[http://dx.doi.org/10.1016/j.bmcl.2009.11.118] [PMID: 20005103]
[71]
Blakemore, D.C.; Bryans, J.S.; Carnell, P.; Field, M.J.; Kinsella, N.; Kinsora, J.K.; Meltzer, L.T.; Osborne, S.A.; Thompson, L.R.; Williams, S.C. Synthesis and in vivo evaluation of 3,4-disubstituted gababutins. Bioorg. Med. Chem. Lett., 2010, 20(1), 248-251.
[http://dx.doi.org/10.1016/j.bmcl.2009.10.121] [PMID: 19910190]
[72]
Corrigan, B.; Feltner, D.E.; Ouellet, D.; Werth, J.L.; Moton, A.E.; Gibson, G. Effect of renal impairment on the pharmacokinetics of PD 0200390, a novel ligand for the voltage-gated calcium channel alpha-2-delta subunit. Br. J. Clin. Pharmacol., 2009, 68(2), 174-180.
[http://dx.doi.org/10.1111/j.1365-2125.2009.03444.x] [PMID: 19694735]
[73]
Kjellsson, M.C.; Ouellet, D.; Corrigan, B.; Karlsson, M.O. Modeling sleep data for a new drug in development using markov mixed-effects models. Pharm. Res., 2011, 28(10), 2610-2627.
[http://dx.doi.org/10.1007/s11095-011-0490-x] [PMID: 21681607]
[74]
Ohashi, K.; Kawai, M.; Ninomiya, N.; Taylor, C.; Kurebayashi, Y. Effect of a new α 2 δ ligand PD-217014 on visceral hypersensitivity induced by 2,4,6-trinitrobenzene sulfonic acid in rats. Pharmacology, 2008, 81(2), 144-150.
[http://dx.doi.org/10.1159/000110737] [PMID: 17989503]
[75]
Wustrow, D.J.; Belliotti, T.R.; Capiris, T.; Kneen, C.O.; Bryans, J.S.; Field, M.J.; Williams, D.; El-Kattan, A.; Buchholz, L.; Kinsora, J.J.; Lotarski, S.M.; Vartanian, M.G.; Taylor, C.P.; Donevan, S.D.; Thorpe, A.J.; Schwarz, J.B. Oxadiazolone bioisosteres of pregabalin and gabapentin. Bioorg. Med. Chem. Lett., 2009, 19(1), 247-250.
[http://dx.doi.org/10.1016/j.bmcl.2008.10.101] [PMID: 19010672]
[76]
Boileau, C.; Martel-Pelletier, J.; Brunet, J.; Schrier, D.; Flory, C.; Boily, M.; Pelletier, J.P. PD-0200347, an α2δ ligand of the voltage gated calcium channel, inhibits in vivo activation of the Erk1/2 pathway in osteoarthritic chondrocytes: A PKCalpha dependent effect. Ann. Rheum. Dis., 2006, 65(5), 573-580.
[http://dx.doi.org/10.1136/ard.2005.041855] [PMID: 16249226]
[77]
Boileau, C.; Martel-Pelletier, J.; Brunet, J.; Tardif, G.; Schrier, D.; Flory, C.; El-Kattan, A.; Boily, M.; Pelletier, J.P. Oral treatment with PD-0200347, an α2δ ligand, reduces the development of experimental osteoarthritis by inhibiting metalloproteinases and inducible nitric oxide synthase gene expression and synthesis in cartilage chondrocytes. Arthritis Rheum., 2005, 52(2), 488-500.
[http://dx.doi.org/10.1002/art.20809] [PMID: 15693013]
[78]
Dixon, S.L.; Smondyrev, A.M.; Rao, S.N. PHASE: A novel approach to pharmacophore modeling and 3D database searching. Chem. Biol. Drug Des., 2006, 67(5), 370-372.
[http://dx.doi.org/10.1111/j.1747-0285.2006.00384.x] [PMID: 16784462]

Rights & Permissions Print Cite
Article Metrics
68
1
© 2024 Bentham Science Publishers | Privacy Policy