Metabotropic glutamate receptor 4 (mGlu 4)-positive allosteric modulators for the treatment of Parkinson's disease: Historical perspective and review of the patent literature

Expert Opinion on Therapeutic Patents

Volumn 22, Issue 5, 2012, Pages 461-481

  Lindsley, Craig W ^a   Hopkins, Corey R ^a  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

CNS; Metabotropic glutamate receptor 4; Non dopaminergic therapies; Parkinson's disease; Positive allosteric modulators

Indexed keywords

1 AMINO 1,3 CYCLOPENTANEDICARBOXYLIC ACID; 2 AMINO 4 PHOSPHONOBUTYRIC ACID; 2 METHYL 6 (2 PHENYLVINYL)PYRIDINE; 2 METHYL 6 (PHENYLETHYNYL)PYRIDINE; ADX 88178; AF 21934; ANTIPARKINSON AGENT; APOMORPHINE; BENSERAZIDE; CPPHA; DOPAMINE; ENTACAPONE; EVOTEC; GLUTAMATE RECEPTOR 4; GLUTAMATE RECEPTOR AGONIST; GLUTAMIC ACID DERIVATIVE; LEVODOPA; LSP1 2111; LSP1 3081; LSP3 2074 I; LSP3 2074 II; LSP4 2022; NEUROPROTECTIVE AGENT; PHOSPHOROUS ACID; PICOLINAMIDE; PRAMIPEXOLE; PRELADENANT; RASAGILINE; ROPINOLE; SELEGILINE; TOLCAPONE; UNCLASSIFIED DRUG; US 0124663; VU 0001171; VU 0050241; VU 0082145; VU 0155041; VU 0359516; VU 0361737; VU 0364439; VU 0364770; VU 0366067; VU 0400195; WO 011722; WO 029104; WO 050305; WO 050316; WO 052169; WO 057208; WO 088406; WO 100607; WO 106526;

ALLOSTERISM; BASAL GANGLION; BINDING SITE; BRAIN DEPTH STIMULATION; CLINICAL TRIAL (TOPIC); DIABETES MELLITUS; DIASTEREOISOMER; DOPAMINERGIC ACTIVITY; DRUG POTENTIATION; GENE EXPRESSION PROFILING; INDUSTRY; LOW DRUG DOSE; NERVOUS SYSTEM INFLAMMATION; NEUROTRANSMITTER RELEASE; NONHUMAN; PAIN; PALLIDOTOMY; PARKINSON DISEASE; PATENT; REVIEW; SCHIZOPHRENIA; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTIPARKINSON AGENTS; BASAL GANGLIA; DRUG DESIGN; EXCITATORY AMINO ACID AGONISTS; HISTORY, 20TH CENTURY; HISTORY, 21ST CENTURY; HUMANS; LEGISLATION, DRUG; MOLECULAR STRUCTURE; NEURAL PATHWAYS; PARKINSON DISEASE; PATENTS AS TOPIC; RECEPTORS, METABOTROPIC GLUTAMATE; STRUCTURE-ACTIVITY RELATIONSHIP; TREATMENT OUTCOME;

EID: 84861523769     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2012.679437     Document Type: Review

References (124)

1. Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron 2003;39:889-909
2. Schapira AHV. Neurobiology and treatment of Parkinson's disease. Trends Pharm Sci 2009;30:41-7
3. Fahn S. Description of Parkinson's disease as a clinical syndrome. Ann NY Acad Sci 2003;991:1-14
4. Parkinson J. An essay on the shaking palsy. Sherwood, Neely and Jones; London: 1817
5. Chaudhuri KR, Healy DG, Schapira AHV. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 2006;5:235-45
6. Smith Y, Wichmann T, Factor SA, et al. Parkinson's disease therapeutics: new developments and challenges since the introduction of levodopa. Neuropsychopharmacol Rev 2012;37:213-46
7. Nisipeanu PF, Korczyn AD. Dopamine agonists. In: Factor SA, Weiner WJ, editiors Parkinson's disease: Diagnosis and clinical management. Demos Medical Publishing; New York: 2002. p. 515-32
8. Warner TT, Schapira AHV. Genetic and environmental factors in the cause of Parkinson's disease. Ann Neurol 2003;53:S16-25
9. Jellinger KA. Recent developments in the pathology of Parkinson's disease. J Neural Transm 2002;62:347-76
10. Carlsson A, Lindqvist M, Magnusson T. 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 1957;180:1200
11. Carlsson A, Lindqvist M, Magnusson T, et al. On the presence of 3-hydroxytyramine in the brain. Science 1958;127:471-2
12. Bertler A, Rosengren E. Occurrence and distribution of catecholamines in brain. Acta Physiol Scand 1959;47:350-61
13. Jankovic J. Parkinson's disease therapy: treatment of early and late disease. Chin Med J 2001;114:227-34
14. Langston JW. The etiology of Parkinson's disease with emphasis on the mptp story. Neurology 1996;47:153S-60S
15. Langston JW, Ballard PA Jr. Parkinson's disease in a chemist working with 1-methyl-4-phenyl-l,2,5,6- tetrahydropyridine. N Engl J Med 1983;309:310-15
16. Funk C. Synthese des d, 1-3-4, dioxyphenylanalnis. Chem Zentralbl 1911:1-3
17. Birkmayer W, Hornykiewicz O. The l-3,4-dihyrdoxyphenylalanine (dopa)- effect in parkinson-akinesia. Wien Klin Wochenschr 1961;73:787-8
18. Barbeau A, Sourkes TL, Murphy CF. Les catecholamines de la maladie de parkinsons. In: de Ajuriaguerra J, editor. Monoamines et Systeme Nervoux Central. Goerg & Cie SA; Geneve: 1962. p. 247-62
19. Hefti FF. Parkinson's disease. In: Drug Discovery for Nervous System Diseases. Wiley-Interscience, Hoboken; NJ: 2005. p. 183-204
20. Baas H, Beiske AG, Ghika J, et al. Catechol-o-methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenom and levodopa requirements in fluctuating parkinsonian patients. Neurology 1998;50:S46-53
21. Stocchi F. The levodopa wearing-off phenomenon in Parkinson's disease: pharmacokinetic considerations. Expert Opin Pharmacother 2006;7:1399-407
22. Lindsley CW. Shipe WD, Wolkenberg SE, et al. Progress towards validating the nmda receptor hypofunction hypothesis of schizophrenia. Curr Top Med Chem 2006;6:771-85
23. Marek K, Jennings D, Seibyl J. Do dopamine agonists or levodopa modify Parkinson's disease progression? Eur J Neurol 2002;9:15-22
24. Leaver KR, Allbutt HN, Creber NJ, et al. Neuroprotective effects of a selective n-methyl-d-aspartate nr2b receptor antagonist in the 6-hydroxydopamine rate model of Parkinson's disease. Clin Exp Pharmacol Physiol 2008;35:1388-94
25. Koller WC. Pharmacologic treatment of parkinsonian tremor. Arch Neurol 1986;43:126-7
26. Shook BC, Jackson PF. Adenosine a2a receptor antagonists and Parkinson's disease. ACS Chem Neurosci 2011;2:555-67
27. Kramer T, Lo Monte F, Goring S, et al. Small molecule kinase inhibitors for lrrk2 and their application to Parkinson's disease models. ACS Chem Neurosci 2012;3:151-160
28. Xiang Z, Thompson AD, Brogan JT, et al. The discovery and characterization of ml218: a novel, centrally active t-type calcium channel inhibitor with robust effects in stn neurons and in a rodent model of parkinson's disease. ACS Chem Neurosci 2011;2:730-42
29. Yang Z-Q, Barrow JC, Shipe WD, et al. Discovery of 1,4-substituted piperidines as potent and selective inhibitors of t-type calcium channels. J Med Chem 2008;51:6471-7
30. Shipe WD, Barrow JC, Yang Z-Q, et al. Design, synthesis, and evaluation of a novel 4-aminomethyl-4-fluoropiperidine as a t-type ca2+ channel antagonist. J Med Chem 2008;51:3692-5
31. Chambers JW, Pachori A, Howard S, et al. Small molecule c-jun-n-terminal kinase inhibitors protect dopaminergic neurons in a model of parkinson's disease. ACS Chem Neurosci 2011;2:198-206
32. Crocker CE, Khan S, Cameron MD, et al. Jnk inhibition protects dopamine neurons and provides behavioral improvement in a rat 6-hydroxydopamine model of parkinson'sdisease. ACS Chem Neurosci 2011;2:207-12
33. Lindsley CW, Emmitte KA. Recent progress in the development of negative allosteric modulators of mglur5. Curr Opin Drug Discov Dev 2009;12:446-57
34. Emmitte KA. Recent advances in the design and development of novel negative allosteric modulators of mglu5. ACS Chem Neurosci 2011;2:Article ASAP-Publication Date (Web): April 15, 2011; DOI: 2010.1021/cn2000266.
35. Hopkins CR, Lindsley CW, Niswender CM. Mglur4-positive allosteric modulation as potential treatment for Parkinson's disease. Future Med Chem 2009;1:501-13
36. Lindsley CW, Niswender CM, Engers DW, et al. Recent progress in the development of mglur4 positive allosteric modulators for the treatment of Parkinson's disease. Curr Top Med Chem 2009;9:949-63
37. Liu KG, Doller D. Progress in the medicinal chemistry of group iii metabotropic glutamate receptors. Ann Rep Med Chem 2011;46:3-17
38. Robichaud AJ, Engers DW, Lindsley CW, et al. Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as cns therapeutics. ACS Chem Neurosci 2011;2:433-49
39. Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends Neurosci 1989;12:366-75
40. Crossman AR. Neural mechanisms in disorders of movement. Comp Biochem Physiol A Comp Physiol 1989;93:141-9
41. DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990;13:281-5
42. Ciliax B, Greenamyre J, Levey A. Functional biochemistry and molecular neuropharmacology of the basal ganglia and motor systems. In: Watts RL, editor. Movement Disorders: Neurological Principles and Practice. McGraw-Hill Professional; New york, NY: 1997. p. 99-118
43. Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalmic nucleus. Science 1990;249:1436-8
44. Wichmann T, DeLong MR. Functional neuroanatomy of the basal ganglia in Parkinson's disease. Adv Neurol 2003;91:9-18
45. Gerfen CR, Engber TM, Mahan LC, et al. D1 and d2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 1990;250:1429-32
46. Braak H, Del Tredici K. Cortico-basal ganglia-circuitry in Parkinson's disease reconsidered. Exp Neurol 2008;212:226-9
47. Benabid AL, Chabardes S, Torres N, et al. Functional neurosurgery for movement disorders: a historical perspective. Prog Brain Res 2009;175:379-91
48. Conn PJ, Lindsley CW, Jones CK. Allosteric modulation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharm Sci 2009;30:25-34
49. Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of gpcrs: a novel approach for the treatment of cns disorders. Nat Rev Drug Dis 2009;8:41-54
50. Hampson DR, Rose EM, Antflick JE. The structures of metabotropic glutamate receptor. In: Gereau RW, IV, Swanson GT, editors. The Glutamate Receptors. Humana Press; New york, NY: 2008. p. 363-86
51. Conn PJ, Pin J-P. Pharmacology and functions of metabotropic glutamate receptors. Ann Rev Pharmacol Toxicol 1997;37:205-37
52. Schoepp DD, Jane DE, Monn JA. Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 1999;38:1431-76
53. Alagarsamy S, Sorensen SD, Conn PJ. Coordinate regulation of mglurs. Curr Opin Neurobiol 2001;3:114-20
54. Cartnell J, Schoepp DD. Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem 2000;75:889-907
55. Kew JNC. Positive and negative allosteric modulation of metabotropic glutamate receptors: emerging therapeutic potential. Pharmacol Ther 2004;104:233-44
56. Bradley SR, Standaert DG, Levey AI, et al. Distribution of group iii mglurs in rat basal ganglia with subtype-specific antibodies. Ann NY Acad Sci 1999;868:531-4
57. Valenti O, Marino MJ, Wittmann M, et al. Group iii metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse. J Neurosci 2003;23:7218-26
58. Wan H, Cahusac PMB. The effects of l-ap4 and l-serine-o-phosphate on inhibition in primary somatosensory cortex of the adult rat in vivo. Neuropharmacology 1995;34:1053-62
59. Agari T, Yasuhara T, Matsui T, et al. Intrapallidal metabotropic glutamate receptor activation in a rat model of Parkinson's disease: behavioral and histological analyses. Brain Res 2008;1203:189-96
60. Konieczny J, Wardas J, Kuter K, et al. The influence of group iii metabotropic glutamate receptor stimulation by (1s,3r,4s)-1-aminocyclopentane- 1,3,4-tricarboxylic acid on the parkinsonian-like akinesia and striatal proenkephalin and prodynorphin mrna expression in rats. Neuroscience 2007;145:611-20
61. Acher FC, Tellier FJ, Azerad R, et al. Synthesis and pharmacological characterization of aminocyclopentanetricarboxylic acids: new tools to discriminate between metabotropic glutamate receptor subtypes. J Med Chem 1997;40:3119-29
62. Selvam C, Goudet C, Oueslati N, et al. L-(+)-2-amino-4- thiophosphonobutyric acid (l-thioap4), a new potent agonist of group iii metabotropic glutamate receptors: increased distal acidity affords enhanced potency. J Med Chem 2007;50:4656-64
63. Filosa R, Marinozzi M, Costantino G, et al. Synthesis and biological evaluation of (2s)- and (2r)-2-(3'-phosphonobicyclo [1.1.1]pentyl)glycines as novel group iii metabotropic glutamate receptor ligands. Bioorg Med Chem 2006;14:3811-17
64. Selvam C, Oueslati N, Lemasson IA, et al. A virtual screening hit reveals newpossibilities for developing group iii metabotropic glutamate receptor agonists. J Med Chem 2010;53:2797-813
65. Wieronska JM, Stachowicz K, Palucha-Poniewiera A, et al. Metabotropic glutamate receptor 4 novel agonist lsp1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and gabaergic systems. Neuropharmacology 2010;59:627-34
66. Beurrier C, Lopez S, Revy D, et al. Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism. FASEB J 2009;23:3619-28
67. Cuomo D, Martella G, Barabino E, et al. Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and gaba transmission in the striatum: implications for parkinson's disease treatment. J Neurochem 2009;109:1096-105
68. Goudet C, Vilar B, Courtiol T, et al. A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential. FASEB J 2012;26:1682-1693
69. Centre National De La Recherche Scientifique (CNRS). WO2007052169; 2007
70. Centre National De La Recherche Scientifique (CNRS). WO2010106526; 2010
71. Melancon BJ, Hopkins CR, Wood MR, et al. Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J Med Chem 2012;55:1445-64
72. Bridges TM, Lindsley CW. G-protein coupled receptors: from classical modes of modulation to allosteric mechanisms. ACS Chem Biol 2008;3:530-41
73. O'Brien JA, Lemaire W, Wittmann M, et al. A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain. J Pharmacol Exp Ther 2004;309:568-77
74. Zhao Z, Wisnoski DD, O'Brien JA, et al. Challenges in the development of mglur5 positive allosteric modulators: the discovery of cppha. Bioorg Med Chem Lett 2007;17:1386-91
75. Annoura H, Fukunaga A, Uesugi M. A novel class of antagonists for metabotropic glutamate receptors, 7-(hydroxyimino)cyclopropa[b]chromen- 1a-carboxylates. Bioorg Med Chem Lett 1996;6:763-6
76. Maj M, Bruno V, Dragic Z, et al. (-)- phccc, a positive allosteric modulator of mglur4: characterization, mechanism of action, and neuroprotection. Neuropharmacology 2003;45:895-906
77. Marino MJ, Williams DL Jr, O'Brien JA, et al. Allosteric modulation of group iii metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment. Proc Natl Acad Sci 2003;100:13668-73
78. Battaglia G, Busceti CL, Molinaro G, et al. Pharmacological activation of mglur4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine. J Neurosci 2006;26:7222-9
79. Williams R, Zhou Y, Niswender CM, et al. Re-exploration of the phccc scaffold: discovery of improved positive allosteric modulators of mglur4. ACS Chem Neurosci 2010;1:411-19
80. Sharma S, Kedrowski J, Rook JM, et al. Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mglu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines. J Med Chem 2009;52:4103-6
81. Utley T, Haddenham D, Salovich JM, et al. Synthesis and sar of a novel metabotropic glutamate receptor 4 (mglu4) antagonist: Unexpected 'molecular switch' from a closely related mglu4 positive allosteric modulator. Bioorg Med Chem Lett 2011;21:6955-69
82. Wood MR, Hopkins CR, Brogan JT, et al. "Molecular switches" on mglur allosteric ligands that modulate modes of pharmacology. Biochemistry 2011;50:2403-10
83. Schann S, Mayer S, Franchet C, et al. Chemical switch of a metabotropic glutamate receptor 2 silent allosteric modulator into dual metabotropic glutamate receptor 2/3 negative/positive allosteric modulators. J Med Chem 2010;53:8775-9
84. Niswender CM, Lebois EP, Luo Q, et al. Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mglur4): part i. Discovery of pyrazolo[3,4-d]pyrimidines as novel mglur4 positive allosteric modulators. Bioorg Med Chem Lett 2008;18:5626-30
85. Williams R, Niswender CM, Luo Q, et al. Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mglur4). Part ii: challenges in hit-to-lead. Bioorg Med Chem Lett 2009;19:962-6
86. Engers DW, Gentry PR, Williams R, et al. Synthesis and sar of novel, 4- (phenylsulfamoyl)phenylacetamide mglu4 positive allosteric modulators (pams) identified by functional high-throughput screening (hts). Bioorg Med Chem Lett 2010;20:5175-8
87. Niswender CM, Johnson KA, Weaver CD, et al. Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol 2008;74:1345-58
88. Christov C, Gonzalez-Bulnes P, Malhaire F, et al. Integrated synthetic, pharmacological, and computational investigation of cis-2-(3,5- dichlorophenylcarbamoyl)- cyclohexanecarboxylic acid enantiomers as positive allosteric modulators of metabotropic glutamate receptor subtype 4. Chem Med Chem 2011;6:131-40
89. Engers DW, Niswender CM, Weaver CD, et al. Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamatereceptor 4 (mglur4) positive allosteric modulators (pams). J Med Chem 2009;52:4115-18
90. Engers DW, Field JR, Le U, et al. Discovery, synthesis, and structure-activity relationship development of a series of n-(4- acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mglu4) with cns exposure in rats. J Med Chem 2011;54:1106-10
91. East SP, Bamford S, Dietz MGA, et al. An orally bioavailable positive allosteric modulator of the mglu4 receptor with efficacy in an animal model of motor dysfunction. Bioorg Med Chem Lett 2010;20:4901-5
92. Hong S-P, Liu KG, Ma G, et al. Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators. J Med Chem 2011;54:5070-81
93. Jones CK, Engers DW, Thompson AD, et al. Discovery, synthesis, and structure-activity relationship development of a series of n-4-(2,5- dioxopyrrolidin-1-yl)phenylpicolinamides (vu0400195, ml182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mglu4) with oral efficacy in an antiparkinsonian animal model. J Med Chem 2011;54:7639-47
94. Engers DW, Le UM, Zhou Z, et al. Discovery and sar development of a novel series of n-4-(2,5-dioxopyrrolidin- 1-yl) phenylpicolinamides, including ml182, as positive allosteric modulators of metabotropic glutamate receptor 4: a novel approach for the treatment of Parkinson's disease. Curr Neuropharm 2011;9(S1):abstract 50
95. Campo B. Novel metabotropic glutamate receptor 4 (mglur4) allosteric potentiators for the treatment of Parkinson's disease and anxiety. Curr Neuropharm 2011;9(S1):abstract 22
96. Celanire S, Bolea C, Bruckner S, et al. Discovery and characterization of novel metabotropic glutamate receptor 4 (mglur4) allosteric potentiators. Curr Neuropharm 2011;9(S1):abstract 24
97. Bennouar K-E, Uberti MA, Bacolod MD, et al. Synergy between l-dopa and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease. Curr Neuropharm 2011;9(S1):abstract 11
98. Uberti MA, Bacolod MD, Jimenez HN, et al. Mglu4 receptor potentiation for the treatment of Parkinson's disease. Curr Neuropharm 2011;9(S1):abstract 173
99. Jones CK, Bubser M, Thompson AD, et al. The mglu4 positive allosteric modulator vu0364770 produces efficacy alone and in combination with l-dopa or an adenosine a2a antagonist in preclinical rodent models of Parkinson's disease. J Pharmacol Exp Ther 2012;340:404-21
100. Niswender CM, Jones CK, Hopkins CR, et al. Mglu4 receptor positive allosteric modulator development for the treatment of cns disorders. Curr Neuropharm 2011;9(S1):abstract 131
101. Merck & Co. WO2010033350; 2010
102. Merck & Co. WO20100033349; 2010
103. Addex Pharma S. A. WO2009010454; 2009
104. Addex Pharma S. A. WO2009010455; 2009
105. Addex Pharma S. A. WO2010079238; 2010
106. Addex Pharma S. A. WO2010079239; 2010
107. Addex Pharma S. A. WO2011010222; 2011
108. Addex Pharma S. A. WO2011086163; 2011
109. Addex Pharma S. A. WO2012009009; 2012
110. Addex Pharma S. A. and Merck Sharp & Dohme Corp. WO2012009001; 2012
111. Addex Pharma S. A. and Merck Sharp & Dohme Corp. WO2012009000; 2012
112. Merck Sharp & Dohme Corp. and Addex Pharma S. A. WO2012006760; 2012
113. Merck Sharp & Dohme Corp. and Addex Pharma S. A. WO2012008999; 2012
114. Domain Therapeutics. WO2011051478; 2011
115. Vanderbilt University. WO2010088406; 2010
116. Vanderbilt University. WO2011011722; 2011
117. Vanderbilt University. WO2011057208; 2011
118. Vanderbilt University. WO2011143466; 2011
119. Vanderbilt University. WO2011029104; 2011
120. Vanderbilt University. US20110124663; 2011
121. Vanderbilt University. WO2011050305; 2011
122. Vanderbilt University. WO2011050316; 2011
123. Vanderbilt University. WO2011100614; 2011
124. Vanderbilt University. WO2011100607; 2011