Novel monoamine oxidase inhibitors: A patent review (2012-2014)

Expert Opinion on Therapeutic Patents

Volumn 25, Issue 1, 2015, Pages 91-110

  Carradori, Simone ^a,b   Petzer, Jacobus P ^c  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

^b UNIVERSITY OF CHIETI   (Italy)

^c NORTH WEST UNIVERSITY   (South Africa)

Author keywords

Alzheimer's disease; Depression; Dual inhibitors; Iron chelation; Monoamine oxidase inhibitors; Natural products; Parkinson's disease

Indexed keywords

ALKALOID DERIVATIVE; BENZOPYRAN DERIVATIVE; INDAZOLE DERIVATIVE; INDOLE DERIVATIVE; LACTONE DERIVATIVE; MONOAMINE OXIDASE INHIBITOR; NATURAL PRODUCT; NITROGEN; POLYCYCLIC DERIVATIVE; UNCLASSIFIED DRUG;

ANTIDEPRESSANT ACTIVITY; BIOLOGICAL ACTIVITY; CLINICAL MEDICINE; DRUG EFFICACY; DRUG FORMULATION; DRUG STRUCTURE; DRUG TARGETING; DRUG TOLERABILITY; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; NEUROLOGIC DISEASE; NONHUMAN; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DESIGN; DRUG INDUSTRY; ENZYMOLOGY; LEGISLATION AND JURISPRUDENCE; NERVOUS SYSTEM DISEASES; PATENT; STRUCTURE ACTIVITY RELATION;

ANIMALS; DRUG DESIGN; DRUG INDUSTRY; HUMANS; MOLECULAR STRUCTURE; MONOAMINE OXIDASE INHIBITORS; NERVOUS SYSTEM DISEASES; PATENTS AS TOPIC; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84919459401     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2014.982535     Document Type: Review

References (128)

1. Shih JC, Chen K, Ridd MJ. Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 1999;22:197-217
2. Walker WH, Kearney EB, Seng RL, Singer TP. The covalently-bound flavin of hepatic monoamine oxidase. Identification and properties of cysteinyl riboflavin. Eur J Biochem 1971;24:328-31
3. Kearney EB, Salach JI, Walker WH, et al. The covalently-bound flavin of hepatic monoamine oxidase. 1. Isolation and sequence of a flavin peptide and evidence for binding at the 8alpha position. Eur J Biochem 1971;24:321-7
4. Edmondson DE, Mattevi A, Binda C, et al. Structure and mechanism of monoamine oxidase. Curr Med Chem 2004;11:1983-93
5. Youdim MB, Bakhle YS. Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness. Br J Pharmacol 2006;147(Suppl 1):S287-96
6. Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 2006;7:295-309
7. Singer TP, Ramsay RR, McKeown K, et al. Mechanism of the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Toxicology 1988;49:17-23
8. Westlund KN, Denney RM, Kochersperger LM, et al. Distinct monoamine oxidase A and B populations in primate brain. Science 1985;230:181-3
9. Fowler CJ, Wiberg A, Oreland L, et al. The effect of age on the activity and molecular properties of human brain monoamine oxidase. J Neural Transm 1980;49:1-20
10. Kalaria RN, Mitchell MJ, Harik SI. Monoamine oxidases of the human brain and liver. Brain 1988;111(Pt 6):1441-51
11. Riachi NJ, Harik SI. Monoamine oxidases of the brains and livers of macaque and cercopithecus monkeys. Exp Neurol 1992;115:212-17
12. Weyler W, Salach JI. Purification and properties of mitochondrial monoamine oxidase type A from human placenta. J Biol Chem 1985;260:13199-207
13. Saura J, Nadal E, Van den Berg B, et al. Localization of monoamine oxidases in human peripheral tissues. Life Sci 1996;59:1341-9
14. Lasbennes F, Sercombe R, Seylaz J. Monoamine oxidase activity in brain microvessels determined using natural and artificial substrates: relevance to the blood-brain barrier. J Cereb Blood Flow Metab 1983;3:521-8
15. Da Prada M, Zürcher G, Wüthrich I, Haefely WE. On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. J Neural Transm Suppl 1988;26:31-56
16. Brown C, Taniguchi G, Yip K. The monoamine oxidase inhibitor-tyramine interaction. J Clin Pharmacol 1989;29:529-32
17. Deftereos SN, Dodou E, Andronis C, Persidis A. From depression to neurodegeneration and heart failure: reexamining the potential of MAO inhibitors. Expert Rev Clin Pharmacol 2012;5:413-25
18. Fernandez HH, Chen JJ. Monoamine oxidase-B inhibition in the treatment of Parkinson's disease. Pharmacotherapy 2007;27(12 Pt 2):174S-85S
19. Finberg JP, Wang J, Bankiewicz K, et al. Increased striatal dopamine production from L-DOPA following selective inhibition of monoamine oxidase B by R (+)-N-propargyl-1-aminoindan (rasagiline) in the monkey. J Neural Transm Suppl 1998;52:279-85
20. Schwartz TL. A neuroscientific update on monoamine oxidase and its inhibitors. CNS Spectr 2013;18(Suppl 1):25-32
21. Lum CT, Stahl SM. Opportunities for reversible inhibitors of monoamine oxidase-A (RIMAs) in the treatment of depression. CNS Spectr 2012;17:107-20
22. Berlin I, Aubin HJ, Pedarriosse AM, et al. Lazabemide in smoking cessation study investigators. Lazabemide, a selective, reversible monoamine oxidase B inhibitor, as an aid to smoking cessation. Addiction 2002;97:1347-54
23. Gesi M, Santinami A, Ruffoli R, et al. Novel aspects of dopamine oxidative metabolism (confounding outcomes take place of certainties). Pharmacol Toxicol 2001;89:217-24
24. Marchitti SA, Deitrich RA, Vasiliou V. Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase. Pharmacol Rev 2007;59:125-50
25. Burke WJ, Kumar VB, Pandey N, et al. Aggregation of alpha-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropathol 2008;115:193-203
26. Fowler JS, Volkow ND, Wang GJ, et al. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging 1997;18:431-5
27. Kaludercic N, Mialet-Perez J, Paolocci N, et al. Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol 2014;73:34-42
28. Mandel S, Weinreb O, Amit T, Youdim MB. Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. Brain Res Brain Res Rev 2005;48:379-87
29. Maruyama W, Akao Y, Carrillo MC, et al. Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. Neurotoxicol Teratol 2002;24:675-82
30. Carrillo MC, Minami C, Kitani K, et al. Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat. Life Sci 2000;67:577-85
31. Kitani K, Kanai S, Ivy GO, Carrillo MC. Pharmacological modifications of endogenous antioxidant enzymes with special reference to the effects of deprenyl: a possible antioxidant strategy. Mech Ageing Dev 1999;111:211-21
32. Stocchi F, Vacca L, Grassini P, et al. Symptom relief in Parkinson disease by safinamide: biochemical and clinical evidence of efficacy beyond MAO-B inhibition. Neurology 2006;67(7 Suppl 2):S24-9
33. Henriot S, Kuhn C, Kettler R, Da Prada M. Lazabemide (Ro 19-6327), a reversible and highly sensitive MAO-B inhibitor: preclinical and clinical findings. J Neural Transm Suppl 1994;41:321-5
34. Bonnet U. Moclobemide: therapeutic use and clinical studies. CNS Drug Rev 2003;9:97-140
35. Provost JC, Funck-Brentano C, Rovei V, et al. Pharmacokinetic and pharmacodynamic interaction between toloxatone, a new reversible monoamine oxidase-A inhibitor, and oral tyramine in healthy subjects. Clin Pharmacol Ther 1992;52:384-93
36. Emilien G. Befloxatone (Synthelabo). IDrugs 1999;2:247-53
37. Lotufo-Neto F, Trivedi M, Thase ME. Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology 1999;20:226-47
38. Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol 2007;152:946-51
39. Gillman PK. Methylene blue implicated in potentially fatal serotonin toxicity. Anaesthesia 2006;61:1013-14
40. Stanford SC, Stanford BJ, Gillman PK. Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of postoperative delirium. J Psychopharmacol 2010;24:1433-8
41. Ramsay RR. Inhibitor design for monoamine oxidases. Curr Pharm Des 2013;19:2529-39
42. Bolasco A, Fioravanti R, Carradori S. Recent development of monoamine oxidase inhibitors. Expert Opin Ther Pat 2005;15:1763-82
43. Bolasco A, Carradori S, Fioravanti R. Focusing on new monoamine oxidase inhibitors. Expert Opin Ther Pat 2010;20:909-39
44. Carradori S, Secci D, Bolasco A, et al. Patent-related survey on new monoamine oxidase inhibitors and their therapeutic potential. Expert Opin Ther Pat 2012;22:759-801
45. Secci D, Bolasco A, Chimenti P, Carradori S. The state of the art of pyrazole derivatives as monoamine oxidase inhibitors and antidepressant/anticonvulsant agents. Curr Med Chem 2011;8:5114-44
46. Secci D, Carradori S, Bolasco A, et al. Discovery and optimization of pyrazoline derivatives as promising monoamine oxidase inhibitors. Curr Top Med Chem 2012;12:2240-57
47. Dart Neuroscience, LLC. Substituted naphthyridine and quinoline compounds as MAO inhibitors. US0315944A1; 2014
48. Helicon Therapeutics. Therapeutic isoxazole compounds. AU202864; 2014
49. "NTZ LAB" LTD. Substituted indazole or indole derivatives as in vitro MAO-B inhibitors. WO107771; 2014
50. Ali NA, Dar BA, Pradhan V, Farooqui M. Chemistry and biology of indoles and indazoles: a mini-review. Mini Rev Med Chem 2013;13:1792-800
51. Breinbauer R, Manger M, Scheck M, Waldmann H. Natural product guided compound library development. Curr Med Chem 2002;9:2129-45
52. Vina D, Serra S, Lamela M, Delogu G. Herbal natural products as a source of monoamine oxidase inhibitors: a review. Curr Top Med Chem 2012;12:2131-44
53. Rajput MS. Natural monoamine oxidase inhibitors: a review. J Pharm Res 2010;3:482-5
54. Carradori S, D'Ascenzio M, Chimenti P, et al. Selective MAO-B inhibitors: a lesson from natural products. Mol Divers 2014;18:219-43
55. Clarke SE, Ramsay RR. Dietary inhibitors of monoamine oxidase A. J Neural Transm 2011;118:1031-41
56. Nat Arboretum Korea Forest Service. Composition comprising the extract of Loranthus yadoriki sieb. having monoamine oxidase-inhibiting activity. KR0089882; 2012
57. Hwang KH, Song I. The inhibitory activity on monoamine oxidase of the fruit of Morus alba. Korean J Pharmacognosy 2003;34:185-9
58. McEwen CM Jr, Cohen JD. An amine oxidase in normal human serum. J Lab Clin Med 1963;62:766-76
59. Liu HB, Zhang H, Li P, et al. Chukrasones A and B: potential Kv1.2 potassium channel blockers with new skeletons from Chukrasia tabularis. Org Lett 2012;14:4438-41
60. Shenguy D. Application of chukrasone A in preparing MAO (monoamine oxidase) inhibitor medicines. CN103356652A; 2013
61. Shenguy D. Application of chukrasone B in preparing MAO (monoamine oxidase) inhibitor medicines. CN103356601A; 2013
62. Cai JY, Zhang Y, Luo SH, et al. Aphanamixoid A, a potent defensive limonoid, with a new carbon skeleton from aphanamixis polystachya. Org Lett 2012;14:2524-7
63. Junhua W. Application of aphanamixoid A to preparation of monoamine oxidase (MAO) inhibitor. CN103120673A; 2013
64. Wang SJ, Li YX, Bao L, et al. Eryngiolide A, a cytotoxic macrocyclic diterpenoid with an unusual cyclododecane core skeleton produced by the edible mushroom Pleurotus eryngii. Org Lett 2012;14:3672-5
65. Junhua W. Application of erymgiolide A in preparing MAO (monoamine oxidase) inhibitor. CN103120674A; 2013
66. Ren J, Zhang F, Liu X, et al. Neonectrolide A, a new oxaphenalenone spiroketal from the fungus Neonectria sp. Org Lett 2012;14:6226-9
67. Aihua S. Application of neonectrolide A in preparing MAO (monoamine oxidase) inhibitor. CN103520155A; 2014
68. Li X, Zhang YF, Zeng X, et al. Two new-skeleton compounds from Sarcandra glabra. Helv Chimica Acta 2012;95:998-1002
69. Shenguy D. Application of sarcaboside A to monoamine oxidase inhibitor. CN103393643A; 2013
70. Shenguy D. Application of sarcaboside B in monoamine oxidase inhibitor drug. CN103356544A; 2013
71. Legoabe LJ, Petzer A, Petzer JP. Inhibition of monoamine oxidase by selected C6-substituted chromone derivatives. Eur J Med Chem 2012;49:343-53
72. Secci D, Carradori S, Bolasco A, et al. Synthesis and selective human monoamine oxidase inhibition of 3-carbonyl, 3-acyl, and 3-carboxyhydrazido coumarin derivatives. Eur J Med Chem 2011;46:4846-52
73. Chimenti F, Bolasco A, Secci D, et al. Synthesis and characterization of new 3-acyl-7-hydroxy-6,8-substituted-coumarin and 3-acyl-7-benzyloxy-6,8-substitutedcoumarin derivatives. J Heterocyclic Chem 2010;47:729-33
74. Chimenti F, Carradori S, Secci D, et al. Synthesis and biological evaluation of novel conjugated coumarin-thiazole systems. J Heterocyclic Chem 2009;46:575-8
75. Chimenti F, Secci D, Bolasco A, et al. Synthesis, molecular modeling, and selective inhibitory activity against human monoamine oxidases of 3-carboxamido-7-substituted coumarins. J Med Chem 2009;52:1935-42
76. Chimenti F, Secci D, Bolasco A, et al. Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of N,N'-bis[2-oxo-2H-benzopyran]-3-carboxamides. Bioorg Med Chem Lett 2006;16:4135-40
77. Ko HH, Jin YJ, Lu TM, Chen IS. A novel monoterpene-stilbene adduct with a 4,4-dimethyl-2,3-diphenylchromane skeleton from Artocarpus xanthocarpus. Chem Biodivers 2013;10:1269-75
78. Changzhou Kelixin Medical Devices CO LTD. Application of Artoxanthochromane to monoamine oxidase (MAO) inhibitor. CN103638011A; 2014
79. Ma SG, RM, Gao et al. Antiviral spirooliganones A and B with unprecedented skeletons from the roots of Illicium oligandrum. Org Lett 2013;15:4450-3
80. Jianshan Y. Application of spirooliganones B in preparation of monoamine oxidase (MAO) inhibitor. CN103462983A; 2013
81. Xiaotao H. Application of Houttuynoid A for preparing MAO (monoamine oxidase) inhibitor medicine. CN102988397A; 2013
82. Wang XJ, Zhang GJ, Zhuang PY, et al. Lycojaponicumins A-C, three alkaloids with an unprecedented skeleton from Lycopodium japonicum. Org Lett 2012;14:2614-17
83. Nanjing Guangkangxie Biolog. Medical Technology CO LTD. Application of Lycojaconicumin A for preparing monoamine oxidase (MAO) inhibitor drugs. CN103479634A; 2014
84. Nanjing Guangkangxie Biolog. Medical Technology CO LTD. Application of Lycojaconicumin B in monoamine oxidase inhibitor medicine. CN103463036A; 2013
85. Nanjing Guangkangxie Biolog. Medical Technology CO LTD. Application of Lycojaconicumin C in monoamine oxidase inhibitor medicine. CN103463079A; 2013
86. Zhang H, Zhang CR, Zhu KK, et al. Fluevirosines A-C: a biogenesis inspired example in the discovery of new bioactive scaffolds from Flueggea virosa. Org Lett 2013;15:120-3
87. Wei G. Application of fluevirosines A in monoamine oxidase inhibitor. CN103463010A; 2013
88. Huang SD, Zhang Y, Cao MM, et al. Myriberine A, a new alkaloid with an unprecedented heteropentacyclic skeleton from Myrioneuron faberi. Org Lett 2012;3:590-3
89. Nanjing Zhengliang Med. Tech. CO. Application of Myriberine A in preparation of monoamine oxidase (MAO) inhibitor. CN103251602A; 2013
90. Ji NY, Liu XH, Miao FP, Qiao MF. Aspeverin, a new alkaloid from an Algicolous strain of Aspergillus versicolor. Org Lett 2013;10:2327-9
91. Zhengmei L. Application of Aspeverin to the preparation of inhibitors of monoamine oxidase (MAO). CN103285012A; 2013
92. Zhao JQ, Wang YM, He HP, et al. Two new highly oxygenated and rearranged limonoids from Phyllantus cochinchinensis. Org Lett 2013;15:2414-17
93. Wenjun Y. Application of compound in preparing monoamine oxidase MAO inhibitor. CN103520185A; 2014
94. Liang CQ, Shi YM, Luo RH, et al. Kadcoccitones A and B, two new 6/6/5/5-fused tetracyclic triterpenoids from Kadsura coccinea. Org Lett 2012;14:6362-5
95. Nanjing Zhengliang Med. Tech. CO. Application of Kadcoccitones A in preparing monoamine oxidase (MAO) inhibitor. CN103463101A; 2013
96. Zeng Q, Guan B, Ren J, et al. Aphanamgrandiol A, a new triterpenoid with a unique carbon skeleton from Aphanamixis grandifolia. Fitoterapia 2013;86:217-21
97. Kang Z. Application of Aphanamgrandiol A in preparing monoamine oxidase (MAO) inhibitor. CN103393675A; 2013
98. Shen YH, Ding Y, Lu T, et al. Incarviatone A, a structurally unique natural product hybrid with a new carbon skeleton from Incarvillea delavayi, and its absolute configuration via calculated electronic circular dichroic spectra. RSC Adv 2012;2:4175-80
99. Nanjing Zhengliang Med. Tech. CO. Application of Incarviatone A in monoamine oxidase inhibitor drug. CN103446096A; 2013
100. Li N, Wu CF, Xu XY, et al. Triterpenes possessing an unprecedented skeleton isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum. Eur J Med Chem 2012;50:173-8
101. Wei J, Junxian W, Liangyu C, et al. Two new dammaran sapogenins from leaves of Panax notoginseng. Planta Med 1982;45:167-71
102. Junhua W. Application of gypensapogenin A in monoamine oxidase (MAO) inhibitor. CN102885825A; 2013
103. Junhua W. Application of gypensapogenin B to preparation of MAO (monoamine oxidase) inhibitor. CN102885830A; 2013
104. Consejo Superior de Investigaciones Cientificas, Universitat Autònoma de Barcelona. Neuroprotective multi-target directed drugs. EP2727916; 2014
105. Mechlovich D, Amit T, Mandel SA, et al. The novel multifunctional, ironchelating drugs M30 and HLA20 protect pancreatic beta-cell lines from oxidative stress damage. J Pharmacol Exp Ther 2010;333:874-82
106. Fowler CJ, Tipton KF. Concentration dependence of the oxidation of tyramine by the two forms of rat liver mitochondrial monoamine oxidase. Biochem Pharmacol 1981;30:3329-32
107. Varinel, Inc. Neuroprotective and neurorestorative iron chelators and monoamine oxidase inhibitors and uses thereof. US0186280; 2014
108. Kaiser C, Lester BM, Zirkle CL, et al. 2-Substituted cyclopropylamines. I. Derivatives and analogs of 2-phenylcyclopropylamine. J Med Chem 1962;5:1243-65
109. Zirkle CL, Kaiser C, Tedeschi DH, et al. 2-Substituted cyclopropylamines. II. Effect of structure upon monoamine oxidase-inhibitory activity as measured in vivo by potentiation of tryptamine convulsions. J Med Chem 1962;5:1265-84
110. Gooden DM, Schmidt DM, Pollock JA, et al. Facile synthesis of substituted trans-2-arylcyclopropylamine inhibitors of the human histone demethylase LSD1 and monoamine oxidases A and B. Bioorg Med Chem Lett 2008;18:3047-51
111. Oryzon Genomics S.A. Selective LSD1 and dual LSD1/MAO-B inhibitors for modulating diseases associated with alterations in protein conformation. WO042042; 2012
112. Robinson DS, Amsterdam JD. The selegiline transdermal system in major depressive disorder: a systematic review of safety and tolerability. J Affect Disord 2008;105:15-23
113. Actavis Group PTC EHF. Pharmaceutical formulations with propargylamine compounds. WO182625; 2013
114. Conopco, Inc., D/B/A Unilever. Frozen confection. WO079964; 2014
115. Valley M, Zhou W, Hawkins EM, et al. A bioluminescent assay for monoamine oxidase activity. Anal Biochem 2006;359:238-46
116. Sviglin KN, Nedicb G, Nikolac M, et al. Insomnia, platelet serotonin and platelet monoamine oxidase in chronic alcoholism. Neurosci Lett 2011;500:172-6
117. Arrojo M, Baca-Garcia E, Perez-Rodriguez MM, et al. Platelet monoamine oxidase activity in obsessivecompulsive disorder. Eur Psychiatry 2007;22:525-9
118. Husain M, Shukla R, Dikshit M, et al. Altered platelet monoamine oxidase-B activity in idiopathic Parkinson's disease. Neurochem Res 2009;34:1427-32
119. Wu JB, Shao C, Li X, et al. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Invest 2014;124:2891-908
120. Tundis R, Loizzo MR, Menichini F. An overview on chemical aspects and potential health benefits of limonoids and their derivatives. Crit Rev Food Sci Nutr 2014;54:225-50
121. Zheng H, Youdim MBH, Fridkin M. Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer's therapy. ACS Chem Biol 2010;5:603-10
122. The Procter and Gamble Co. Use of monoamine oxidase inhibitors to improve epithelial biology. WO051374; 2012
123. Brandon University. (-)-Deprenyl and related compounds for the treatment of alopecia. WO056070; 2014
124. Teikoku Pharma USA, Inc. Methods for the treatment of skin neoplasms. WO070526; 2013
125. University of Southern California. Monoamine oxidase inhibitors and methods for treatment and diagnosis of prostate cancer. WO016580; 2013
126. Yissum Research Development Company of the Hebrew University of Jerusalem LTD. Ladostigil therapy for immunomodulation. WO118126; 2013
127. University of Padua. Treatment of muscular dystrophies and associated conditions by administration of monoamine oxidase inhibitors. US0329800; 2012
128. Tonix Pharmaceuticals, Inc. Treatment for cocaine addiction. WO050594; 2012