Small molecules targeting sodium and calcium channels for neuropathic pain

Current Opinion in Drug Discovery and Development

Volumn 12, Issue 4, 2009, Pages 543-561

  Bear, Brian ^a   Asgian, Juliana ^a   Termin, Andreas ^a   Zimmermann, Nicole ^a  

^a VERTEX PHARMACEUTICALS   (United States)

Author keywords

CaV2.2; CaV3.1; Calcium channel; N type; NaV1.3; NaV1.7; NaV1.8; Neuropathic pain; Sodium channel; T type; Use dependent blocker; Voltage gated

Indexed keywords

A 703467; A 803467; AMIDE; APJ 2708; BENZAZEPINE DERIVATIVE; CALCIUM CHANNEL BLOCKING AGENT; CARBAMAZEPINE; CDA 54; CILNIDIPINE; CYCLOHEXYLPIPERAZINE DERIVATIVE; CYCLOPENTANE DERIVATIVE; DULOXETINE; FURAN DERIVATIVE; GABAPENTIN; HETEROCYCLIC COMPOUND; IMIDAZOPYRIDINE DERIVATIVE; KYS 05044; KYS 05090; LAMOTRIGINE; LIDOCAINE; MK 6721; N (THIAZOL 2 YL)BENZENESULFONAMIDE; NMED 160; OMEGA CONOTOXIN CVID; OMEGA CONOTOXIN MVIIA; PIPERAZINE DERIVATIVE; PREGABALIN; PYRAZINE DERIVATIVE; PYRIDINE DERIVATIVE; PYRROLIDINE 2 CARBOXAMIDE; RALFINAMIDE; SODIUM CHANNEL BLOCKING AGENT; TETRAHYDROISOQUINOLINE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VH 04; VOLTAGE GATED CALCIUM CHANNEL; VOLTAGE GATED SODIUM CHANNEL;

ALLODYNIA; ARTICLE; CLINICAL TRIAL; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG POTENCY; DRUG SAFETY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; DRUG TOLERABILITY; HUMAN; NEUROPATHIC PAIN; NONHUMAN; PAIN; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; STRUCTURE ANALYSIS;

ANIMALS; CALCIUM CHANNEL BLOCKERS; CALCIUM CHANNELS; HUMANS; MOLECULAR STRUCTURE; NEURALGIA; PAIN; PERIPHERAL NERVOUS SYSTEM DISEASES; SMALL MOLECULE LIBRARIES; SODIUM CHANNEL BLOCKERS; SODIUM CHANNELS;

EID: 67649948710     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (85)

1. Torrance N, Smith BH, Bennett MI, Lee AJ: The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain (2006) 7(4):281-289.
2. Bouhassira D, Lantéri-Minet M, Attal N, Laurent B, Touboul C: Prevalence of chronic pain with neuropathic characteristics in the general population. Pain (2008) 136(3):380-387.
3. Dworkin RH: An overview of neuropathic pain: Syndromes, symptoms, signs, and several mechanisms. Clin J Pain (2002) 18(6):343-349.
4. Catterall WA, Goldin AL, Waxman SG: International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev(2005) 57(4):397-409. · Presents an overview of the biochemical, molecular and genetic properties, physiological roles and pharmacological significance of the voltage-gated sodium channels.
5. Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J: International Union of Pharmacology. XLVIII. Nomenclature and structurefunction relationships of voltage-gated calcium channels.Pharmacol Rev (2005) 57(4):411-425. · Describes the biochemical, molecular and genetic properties, physiological roles and pharmacological significance of the voltage-gated calcium channels.
6. Rogers M, Tang L, Madge DJ, Stevens EB: The role of sodium channels in neuropathic pain. Semin Cell Dev Biol (2006) 17(5): 571-581.
7. Anger T, Madge DJ, Mulla M, Riddall D: Medicinal chemistry of neuronal voltage-gated sodium channel blockers. J Med Chem(2001) 44(2):115-137.
8. Kyle DJ, Ilyin VI: Sodium channel blockers. J Med Chem (2007) 50(11):2583-2588.
9. Catterall WA: Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol (2000) 16:521-555.
10. Nau C, Wang GK: Interactions of local anesthetics with voltagegated Na+ channels. J Membr Biol (2004) 201(1):1-8.
11. Gilron I, Watson CP, Cahill CM, Moulin DE: Neuropathic pain: A practical guide for the clinician. Can Med Assoc J (2006) 175(3):265-275.
12. Silver M, Blum D, Grainger J, Hammer AE, Quessy S: Doubleblind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain. J Pain Symptom Manage (2007) 34(4):446-454.
13. Shao PP, Ok D, Fisher MH, Garcia ML, Kaczorowski GJ, Li C, Lyons KA, Martin WJ, Meinke PT, Priest BT, Smith MM et al: Novel cyclopentane dicarboxamide sodium channel blockers as a potential treatment for chronic pain. Bioorg Med Chem Lett (2005) 15(7):1901-1907. · Describes the evolution of the NaV1.7 blocker BPBTS into a cyclopentane dicarboxamide NaV1.7 blocker CDA-54 with improved PK profile and activity similar to mexiletine in the SNL model.
14. Brochu RM, Dick IE, Tarpley JW, McGowan E, Gunner D, Herrington J, Shao PP, Ok D, Li C, Parsons WH, Stump GL et al: Block of peripheral nerve sodium channels selectively inhibits features of neuropathic pain in rats. Mol Pharmacol (2006) 69(3):823-832.
15. Ok D, Li C, Abbadie C, Felix JP, Fisher MH, Garcia ML, Kaczorowski GJ, Lyons KA, Martin WJ, Priest BT, Smith MM et al: Synthesis and SAR of 1,2-trans-(1-hydroxy-3-phenylprop-1-yl)cyclopentane carboxamide derivatives, a new class of sodium channel blockers. Bioorg Med Chem Lett (2006) 16(5):1358-1361. · Describes efforts to address the metabolic liabilities of NaV1.7 blocker CDA-54. A new class of NaV1.7 blockers, the 1,2-trans-(1-hydroxy-3- phenylprop-1-yl) cyclopentane carboxamides, exhibit similar in vitro activity and improved PK profile compared with CDA-54.
16. Hoyt SB, London C, Gorin D, Wyvratt MJ, Fisher MH, Abbadie C, Felix JP, Garcia ML, Li X, Lyons KA, McGowan E et al: Discovery of a novel class of benzazepinone Nav1.7 blockers: Potential treatments for neuropathic pain. Bioorg Med Chem Lett (2007) 17(16):4630-4634. ·· Describes a series of benzazepinone NaV1.7 blockers that demonstrated oral efficacy in a rat model for neuropathic pain.
17. Hoyt SB, London C, Ok H, Gonzalez E, Duffy JL, Abbadie C, Dean B, Felix JP, Garcia ML, Jochnowitz N, Karanam BV et al: Benzazepinone NaV1.7 blockers: Potential treatments for neuropathic pain.Bioorg Med Chem Lett (2007) 17(22):6172-6177. ·· A follow-up paper to reference [17]. The compounds in this paper have improved bioavailability and exposure when compared to the benzazepinones discussed in reference [17]. In addition, two compounds from this series exhibited good efficacy in a rat model for neuropathic pain.
18. Williams BS, Felix JP, Priest BT, Brochu RM, Dai K, Hoyt SB, London C, Tang YS, Duffy JL, Parsons WH, Kaczorowski GJ et al: Characterization of a new class of potent inhibitors of the voltage-gated sodium channel NaV1.7. Biochemistry (2007) 46(50):14693-14703.
19. London C, Hoyt SB, Parsons WH, Williams BS, Warren VA, Tschirret-Guth R, Smith MM, Priest BT, McGowan E, Martin WJ, Lyons KA et al: Imidazopyridines: A novel class of hNaV1.7 channel blockers. Bioorg Med Chem Lett (2008) 18(5):1696-1701.
20. Ilyin VI, Hodges DD, Whittemore ER, Carter RB, Cai SX, Woodward RM: V102862 (Co 102862): A potent, broadspectrum state-dependent blocker of mammalian voltagegated sodium channels. Br J Pharmacol (2005) 144(6):801-812.
21. Ilyin VI, Pomonis JD, Whiteside GT, Harrison JE, Pearson MS, Mark L, Turchin PI, Gottshall S, Carter RB, Nguyen P, Hogenkamp DJ et al: Pharmacology of 2-[4-(4-chloro-2- fluorophenoxy)phenyl]-pyrimidine-4- carboxamide: A potent, broad-spectrum state-dependent sodium channel blocker for treating pain states. J Pharmacol Exp Ther (2006) 318(3):1083- 1093.
22. Ye F, Shao P: Novel biaryl pyrazinone amides as hNaV1.7 blockers for the treatment of neuropathic pain. ACS (2007) 234: MEDI-143.
23. Kort ME, Drizin I, Gregg RJ, Scanio MJ, Shi L, Gross MF, Atkinson RN, Johnson MS, Pacofsky GJ, Thomas JB, Carroll WA et al: Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the NaV1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain.J Med Chem (2008) 51(3):407-416. ·· Discusses the first example of NaV1.8-selective compounds, the 5-aryl- 2-furfuramides. Additionally, several compounds in this series exhibited efficacy in three rat pain models.
24. Browne LE, Blaney FE, Yusaf SP, Clare JJ, Wray D: Structural determinants of drugs acting on the NaV1.8 channel.J Biol Chem (2009) 284(16):10523-10536. · Presents data suggesting that A-803467 binds, at least partially, to the anesthetic binding site of NaV1.8 .
25. Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, Kort M, Carroll W, Marron B, Atkinson R, Thomas J et al: A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci USA (2007) 104(20):8520-8525.
26. Drizin I, Gregg RJ, Scanio MJC, Shi L, Marron BE, Atkinson RN, Thomas JB, Johnson MS, Pacofsky GJ, Secrest ME, Kort ME et al: Discovery and SAR of furan piperazines as sodium channel blockers for the treatment of neuropathic pain. ACS (2007) 233:MEDI-316.
27. Scanio MJC, Shi L, Kort ME, Drizin I, Gregg RJ, Thomas JB, Atkinson RN, Johnson MS, Marron BE, Chapman ML, Liu D et al: Potent, selective pyrazine-based blockers of the NaV1.8 (PN3) sodium channel. ACS (2007) 233:MEDI-321.
28. Marron BE, Atkinson RN, Thomas JB, Johnson MS, Pacofsky GJ, Secrest ME, Shi L, Kort ME, Drizin I, Scanio MJC, Gregg RJ et al: SAR development of potent, selective pyridine-based blockers of the NaV1.8 (PN3) sodium channel. ACS (2007) 233:MEDI-319.
29. Goldberg YP, MacFarlane J, MacDonald ML, Thompson J, Dube MP, Mattice M, Fraser R, Young C, Hossain S, Pape T, Payne B et al: Loss-of-function mutations in the NaV1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet (2007) 71(4):311-319. ·· Reports that loss of NaV1.7 function leads to pain indifference in humans. This article has generated much interest in the pain scientific community.
30. Reddy NL, Fan W, Magar SS, Perlman ME, Yost E, Zhang L, Berlove D, Fischer JB, Burke-Howie K, Wolcott T, Durant GJ: Synthesis and pharmacological evaluation of N,N'- diarylguanidines as potent sodium channel blockers and anticonvulsant agents. J Med Chem (1998) 41(17):3298-3302.
31. Dunlop J, Bowlby M, Peri R, Tawa G, LaRocque J, Soloveva V, Morin J: Ion channel screening. Comb Chem High Throughput Screen(2008) 11(7):514-522.
32. Lu Q, An WF: Impact of novel screening technologies on ion channel drug discovery. Comb Chem High Throughput Screen(2008) 11(3):185-194.
33. Kaczorowski GJ, McManus OB, Priest BT, Garcia ML: Ion channels as drug targets: The next GPCRs. J Gen Physiol (2008) 131(5):399- 405.
34. McGivern JG: Targeting N-type and T-type calcium channels for the treatment of pain. Drug Disc Today (2006) 11(5-6): 245-253. · Discusses the N-type and T-type voltage-gated calcium channels as targets for the treatment of pain (see also reference [38]).
35. Gribkoff VK: The role of voltage-gated calcium channels in pain and nociception. Semin Cell Dev Biol (2007) 17(5):555-564.
36. Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, Fisher R, Bryce DA, Mangieri EA, Luther RR, Mayo M et al: Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: A randomized controlled trial. J Am Med Assoc (2004) 291(1):63-70.
37. Smith MT, Cabot PJ, Ross FB, Robertson AD, Lewis RJ: The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices.Pain (2002) 96(1-2):119-127. · Discusses the N-type and T-type voltage-gated calcium channels as targets for the treatment of pain (see also reference [35]).
38. Flinn JP, Pallaghy PK, Lew MJ, Murphy R, Angus JA, Norton RS: Roles of key functional groups in ω-conotoxin GVIA synthesis, structure and functional assay of selected peptide analogues. Eur J Biochem (1999) 262(2):447-455.
39. Liu Z, Dai J, Dai L, Deng M, Hu Z, Hu W, Liang S: Function and solution structure of Huwentoxin-X, a specific blocker of N-type calcium channels, from the Chinese bird spider Ornithoctonus huwena. J Biol Chem (2006) 281(13):8628-8635.
40. Neuromed, Merck Discontinue Pain Drug Candidate: Contract Pharma, Rodman Publishing, Ramsey, NJ, USA (2007). contractpharma. com/news/2007/08/08/
41. Yamamoto T, Niwa S, Ohno S, Onishi T, Matsueda H, Koganei H, Uneyama H, Fujita S-i, Takeda T, Kito M, Ono Y et al: Structureactivity relationship study of 1,4-dihydropyridine derivatives blocking N-type calcium channels. Bioorg Med Chem Lett (2006) 16(4):798-802.
42. Yamamoto T, Niwa S, Ohno S, Tokumasu M, Masuzawa Y, Nakanishi C, Nakajo A, Onishi T, Koganei H, Fujita S, Takeda T et al: The structure-activity relationship study on 2-, 5-, and 6-position of the water soluble 1,4-dihydropyridine derivatives blocking N-type calcium channels. Bioorg Med Chem Lett (2008) 18(17):4813-4816.
43. Yamamoto T, Niwa S, Iwayama S, Koganei H, Fujita S-i, Takeda T, Kito M, Ono Y, Saitou Y, Takahara A, Iwata S et al: Discovery, structure-activity relationship study, and oral analgesic efficacy of cyproheptadine derivatives possessing N-type calcium channel inhibitory activity. Bioorg Med Chem (2006) 14(15):5333-5339.
44. Baell JB, Duggan PJ, Forsyth SA, Lewis RJ, Lok YP, Schroeder CI, Shepherd NE: Synthesis and biological evaluation of anthranilamide-based non-peptide mimetics of ω-conotoxin GVIA. Tetrahedron (2006) 62(31):7284-7292.
45. McGivern JG: Pharmacology and drug discovery for T-type calcium channels. CNS Neurol Disord Drug Targets (2006) 5(6): 587-603.
46. Nelson MT, Todorovic SM, Perez-Reyes E: The role of T-type calcium channels in epilepsy and pain. Curr Pharm Des (2006) 12(18):2189-2197.
47. Asirvatham S, Sebastian C, Thadani U: Choosing the most appropriate treatment for stable angina. Safety considerations. Drug Saf (1998) 19(1):23-44.
48. Rhim H, Lee YS, Park SJ, Chung BY, Lee JY: Synthesis and biological activity of 3,4-dihydroquinazolines for selective T-type Ca2+ channel blockers. Bioorg Med Chem Lett (2005) 15(2):283-286.
49. Seo HN, Choi JY, Choe YJ, Kim Y, Rhim H, Lee SH, Kim J, Joo DJ, Lee JY: Discovery of potent T-type calcium channel blocker.Bioorg Med Chem Lett (2007) 17(21):5740-5743.
50. Doddareddy MR, Choo H, Cho YS, Rhim H, Koh HY, Lee J-H, Jeong S-W, Pae AN: 3D pharmacophore based virtual screening of T-type calcium channel blockers. Bioorg Med Chem (2007) 15(2):1091-1105.
51. Hangeland JJ, Cheney DL, Friends TJ, Swartz S, Levesque PC, Rich AJ, Sun L, Bridal TR, Adam LP, Normandin DE, Murugesan N et al: Design and SAR of selective T-type calcium channel antagonists containing a biaryl sulfonamide core. Bioorg Med Chem Lett (2008) 18(2):474-478.
52. Lee HK, Lee YS, Roh EJ, Rhim H, Lee JY, Shin KJ: Synthesis and evaluation of α,α-disubstituted phenylacetate derivatives for T-type calcium channel blockers. Bioorg Med Chem Lett (2008) 18(15):4424-4427.
53. Shipe WD, Barrow JC, Yang ZQ, Lindsley CW, Yang FV, Schlegel KA, Shu Y, Rittle KE, Bock MG, Hartman GD, Tang C et al: Design, synthesis, and evaluation of a novel 4-aminomethyl-4- fluoropiperidine as a T-type Ca2+ channel antagonist.J Med Chem (2008) 51(13):3692-3695.
54. Yang ZQ, Barrow JC, Shipe WD, Schlegel KA, Shu Y, Yang FV, Lindsley CW, Rittle KE, Bock MG, Hartman GD, Uebele VN et al: Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels. J Med Chem(2008) 51(20):6471-6477.
55. Vertex Pharmaceuticals Inc (Kawatkar AS, Whitney T, Neubert TD, Zimmermann N, Termin AP, Martinborough E): Bicyclic derivatives as modulators of ion channels. WO-2006122014 (2006).
56. Icagen Inc (Wang X, Fulp A, Marron B, Beaudoin S, Seconi D, Suto M): Inhibitors of ion channels. WO-2007056099 (2007).
57. Glaxo Wellcome plc (Alvaro G, Amantini D, Bergauer M, Bonetti F, Profeta R): Quaternary α-aminocarboxamides derivatives as modulators of voltage-gated sodium channels. WO-2007042240 (2007).
58. Xenon Pharmaceuticals Inc (Fraser RA, Sherrington R,. Macdonald ML, Samuels M, Newman S, Fu J-M, Kamboj R): Potent and selective NaV1.7 sodium channel blockers. WO-2007109324 (2007).
59. Astrazeneca AB (Besidski Y, Claesson A): Phenyl-1,2,3,4- tetrahydroisoquinolines derivatives and their use in the treatment of a pain disorder. WO-2009005459 (2009).
60. Astrazeneca AB (Besidski Y, Claesson A): Small molecule inhibitors of NaV1.7 sodium channels for the treatment of pain disorders.WO-2009005460 (2009).
61. Astrazeneca AB; Astrazeneca UK LT D (Besidski Y, Claesson A, Macsari I, Sandberg L): New compounds 955. WO-2009010784 (2009).
62. Astrazeneca AB (Besidski Y, Gravenfors Y, Kers I, Skogholm K, Svensson M): Preparation of 3-oxoindole-1-carboxamides as analgesic agents. WO-200800820 (2008).
63. Astrazeneca AB (Besidski Y, Claesson A, Csjernyik G, Gravenfors Y, Kers I, Skogholm K, Sohn D): New compounds 805.WO-2008130319 (2008).
64. Vertex Pharmaceuticals Inc (Joshi P, Krenitsky P, Gonzalez J, Wang J, Wilson D, Termin A): Preparation of N-(3-sulfamoylphenyl) benzamides useful as inhibitors of voltage-gated sodium channels. US-2007238733 (2007).
65. Pfizer Ltd (Gibson KR, Poinsard C, Glossop MS, Kemp MI): Pyrazine derivatives. WO-2007052123 (2007).
66. Pfizer Ltd (Bagal SK, Gibson KR, Kemp MI, Poinsard C, Stammen BL, Denton SM, Glossop MS): Pyridine derivatives. WO-2008135826 (2008).
67. Pfizer Ltd (Kemp MI): N-[6-amino-S-(phenyl)pyrazin-2-yl]- isoxazole-4-carboxamide derivatives and related compounds as NaV1.8 channel modulators for the treatment of pain.WO-2008135830 (2008).
68. Vernalis Research Ltd (Hamlyn R, Addison G, Earnshaw CG, Finch H, Huckstep M, Lynch R, Mellor S): Azacyclic compounds as inhibitors of sensory neurone specific sodium channels.WO-2007007069 (2007).
69. Vernalis Research Ltd (Hamlyn R, Callis D, Earnshaw CG, Finch H, Huckstep M, Lynch R, Mellor S): Antagonists of SNS sodium channels. WO-2007007057 (2007).
70. Neuromed Pharmaceuticals Inc (Pajouhesh H, Ding Y): Heterocyclic compounds as calcium channel blockers. WO 2007137417 (2007).
71. Neuromed Pharmaceuticals Inc (Pajouhesh H, Kaul R, Ding Y, Hum G, Pajouhesh H): Heterocyclic amide derivatives as calcium channel blockers. WO-2007071035 (2007).
72. Euro-Celtique SA (Yao J, Shao B, Kyle DJ, Sha D, Chen Z, Islam K, Zhou X): Benzenesulfonamide compounds and their use as blockers of calcium channels. WO-2007118853 (2007).
73. Neuromed Pharmaceuticals Inc (Pajouhesh H, Holland R, Pajouhesh H): Isoxazole derivatives as calcium channel blockers. WO-2007118323 (2007).
74. Neuromed Pharmaceuticals Inc (Pajouhesh H, Ding Y, Pajouhesh H, Holland R, Hum G): Diaryl piperidine compound as calcium channel blockers. WO-2008031227 (2008).
75. Shionogi & Co Ltd; Euroceltique SA (Matsumura A, Mikamiyama H, Tsuno N, Kyle DJ, Shao B, Yao J): Oxime compounds and the use thereof. WO-2008008398 (2008).
76. Euroceltique SA ; Shionogi & Co Ltd (Matsumura A, Mikamiyama H, Yao J): Amide compounds and the use thereof. WO-2008150447 (2008).
77. Pfizer Japan Inc; Pfizer Inc (Inoue T, Noguchi H, Sakurada I, Tatsuta M): Sulfonamide compounds. WO-2007125398 (2007).
78. Korea Institute of Science & Technology (Hahn H-G, Shin D-Y, Nam K-D): Novel thiazole-based compound and inhibitor of T-type calcium channel containing the same. WO-2008018655 (2008).
79. Korea Institute of Science & Technology (Nam G-S, Choi K-I, Koh H-Y, Pae A-N, Rhim H-W, Choi I-S): Piperazinylalkylpyrazole derivatives useful as selective T-type calcium channel blockers and preparation method thereof. EP-01757590 (2007).
80. Icagen Inc (Pacofsky GJ, Suto MJ, Fritch PC): Calcium channel antagonists. WO-2007075852 (2007).
81. Icagen Inc (Pacofsky GJ, Suto MJ, Fritch PC): Calcium channel antagonists. WO-2007073497 (2007).
82. Merck & Co Inc (Barrow JC, Bieber K-AS, Cube RV, Mattern MC, Reger TS, Shu Y, Yang Z-Q): Pyridyl amide T-type calcium channel antagonists. WO-2007120729 (2007).
83. Merck & Co Inc (Chakravarty PK, Duffy JL, Park MK, Tyagarajan S, Zhou B): 2-Substituted indole derivatives as calcium channel blockers. WO-2008133867 (2008).
84. Pajouhesh H, Pajouhesh H, Ding Y, Tan J, Grimwood M, Belardetti F, Kaul R: Preparation of bicyclic pyrimidine derivatives as calcium channel blockers. US-2008280900 (2008).
85. Pfizer Products Inc (Bornemeier DA, Cai C, Fors KS, Hagen TJ, Holsworth DD, Jalaie M, Leonard DM, Moody TS, Take Y): Oxadiazole compounds as calcium channel antagonists. WO-2008050200 (2008).