Multi-Target Drugs. Strategies and Challenges for Medicinal Chemists

The Practice of Medicinal Chemistry

Volumn , Issue , 2008, Pages 549-571

  Morphy, Richard ^a   Rankovic, Zoran ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 69949111533     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1016/B978-0-12-374194-3.00027-5     Document Type: Chapter

References (77)

1. Kola I., Landis J. Can the pharmaceutical industry reduce attrition rates?. Nat. Rev. Drug Discov. 2004, 3:711-716.
2. Morphy R., Kay C., Rankovic Z. From magic bullets to designed multiple ligands. Drug Discov. Today 2004, 9:641-651.
3. Millan M.J. Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol. Ther. 2006, 110:135-370.
4. Keith C.T., Borisy A.A., Stockwell B.R. Multicomponent therapeutics for networked systems. Nat. Rev. Drug. Discov. 2005, 4:1-7.
5. Law M.R., Wald J., Morris J.K., Jordan R.E. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. Br. Med. J. 2003, 326:1427-1431.
6. Larder B.A., Kemp S.D., Harrigan P.R. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 1995, 269:696-699.
7. Eisen S.A., Miller D.K., Woodward R.S., Spitznagel E., Przybeck T.R. The effect of prescribed daily dose frequency on patient medical compliance. Arch. Intern. Med. 1990, 150:1881-1884.
8. Skolnik N.S., Beck J.D., Clark M. Combination antihypertensive drugs: recommendations for use. Am. Fam. Physician 2000, 61:3049-3056.
9. Glass G. Cardiovascular combinations. Nat. Rev. Drug. Discov. 2004, 3:731-732.
10. Herrick T.M., Million R.P. From the analyst's couch: tapping the potential of fixed-dose combinations. Nat. Rev. Drug. Discov. 2007, 6:513-514.
11. Edwards I.R., Aronson J.K. Adverse drug reactions: definitions diagnosis and management. Lancet 2000, 356:1255-1259.
12. 4 dopamine receptor antagonist (L-745, 870) in acutely psychotic inpatients with schizophrenia. Arch. Gen. Psychiatry 1997, 54:567-572.
13. Campiani G., Butini S., Fattorusso C., Catalanotti B., Gemma S., Nacci V., Morelli E., Cagnotto A., Mereghetti I., Mennini T., Carli M., Minetti P., Di Cesare M.A., Mastroianni D., Scafetta N., Galletti B., Stasi M.A., Castorina M., Pacifici L., Vertechy M., Di Serio S., Ghirardi O., Tinti O., Carminati P. Pyrrolo[1,3]benzo-thiazepine-based serotonin and dopamine receptor antagonists. Mole-cular modeling, further structure-activity relationship studies, and identification of novel atypical antipsychotic agents. J. Med. Chem. 2004, 47:143-157.
14. Jones H.M., Pilowsky L.S. New targets for antipsychotics. Expert Rev. Neurother. 2002, 2:61-68.
15. Stahl S.M., Entsuah R., Rudolph R.L. Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression. Biol. Psychiatry 2002, 202:1166-1174.
16. Charlier C., Michaux C. Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer non-steroidal anti-inflammatory drugs. Eur. J. Med. Chem. 2003, 38:645-659.
17. Chao, R., Rapta, M., Colson, P. J., Lee, J. US Patent 0182092, 2005.
18. Investigational Drugs Database, 590916.
19. 1A and 5-HT re-uptake ligands. Bioorg. Med. Chem. Lett. 1999, 9:3243-3248.
20. Mewshaw R., Meagher K., Zhou P., Zhou D., Shi X., Scerni R., Smith D., Schechter L., Andree T. Studies toward the discovery of the next generation of antidepressants. Part 2: incorporating a 5-HT1A antagonist component into a class of serotonin reuptake inhibitors. Bioorg. Med. Chem. Lett. 2002, 12:307-310.
21. 1 antagonists-serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants. Bioorg. Med. Chem. Lett. 2002, 12:261-264.
22. Lowe J., Seeger T., Nagel A., Howard H., Seymour P., Heym J., Ewing F., Newman M., Schmidt A. 1-Naphthylpiperazine derivatives as potential atypical antipsychotic agents. J. Med. Chem. 1991, 34:1860-1866.
23. Howard H., Lowe J., Seeger T., Seymour P., Zorn S., Maloney P., Ewing F., Newman M., Schmidt A., Furman J., Robinson G., Jackson E., Johnson C., Morrone J. 3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents. J. Med. Chem. 1996, 39:143-148.
24. 4 receptor antagonists. Part 1: identification and structure-activity relationships. Bioorg. Med. Chem. Lett. 2002, 12:3105-3109.
25. 4 receptor antagonists. Part 2: asymmetric synthesis and biological evaluation. Bioorg. Med. Chem. Lett. 2002, 12:3111-3115.
26. Vincenzo Garzya Ian T.F., Gribble A.D., Hadley M.S., Lightfoot A.P., Payne A.H., Smith A.B., Douglas S.E., Cooper D.G., Stansfield I.G., Meeson M., Dodds E.E., Jones D.N.C., Wood M., Reavill C., Scorer C.A., Worby A., Riley G., Eddershaw P., Ioannou C., Donati D., Hagan J.J., Ratti E.A. Studies towards the identification of a new generation of atypical antipsychotic agents. Bioorg. Med. Chem. Lett. 2007, 17:400-405.
27. Robl J., Sieber-McMaster E., Asaad M.M., Bird J.E., Delaney N.G., Barrish J.C., Neubeck R., Natarajan S., Cohen M., Rovnyak G.C., Huber G., Murugesan N., Girotra R., Cheung H.S., Waldron T., Petrillo E.W. Mercaptoacyl dipeptides as dual inhibitors of angioten-sin converting enzyme and neutral peptidase. Preliminary structure-activity studies. Bioorg. Med. Chem. 1994, 4:1783-1789.
28. Robl J.A., Sun C.-Q., Stevenson J., Ryono D.E., Simpkins L.M., Cimarusti M.P., Dejneka T., Slusarchuk W.A., Chao S., Stratton L., Misra R.N., Bednarz M.S., Asaad M.M., Cheung H.S., Abboa-Offei B.E., Smith P.L., Mathers P.D., Fox M., Schaeffer T.R., Seymour A.A., Trippodo N.C. Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J. Med. Chem. 1997, 40:1570-1577.
29. Murugesan N., Tellew J., Gu Z., Kunst B., Fadnis L., Cornelius L., Baska R., Yang Y., Beyer S., Monshizadegan H., Dickinson K., Panchal B., Valentine M., Chong S., Morrison R., Carlson K., Powell J., Moreland S., Barrish J., Kowala M., Macor J. Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists. J. Med. Chem. 2002, 45:3829-3835.
30. Eiser N. Histamine antagonists and asthma. Pharm. Ther. 1982, 17:239-250.
31. 1 dual antagonizing activity, 1. J. Med. Chem. 1993, 36:417-420.
32. Lewis T., Bayless L., Eckman J., Ellis J., Grewal G., Libertine L., Nicolas J., Scannell R., Wels B., Wenberg K., Wypij D. 5-Lipoxygenase inhibitors with histamine H1 receptor antagonist activity. Bioorg. Med. Chem. Lett. 2004, 14:2265-2268.
33. Toda N., Tago K., Marumoto S., Takami K., Ori M., Yamada N., Koyama K., Naruto S., Abe K., Yamazaki R., Hara T., Aoyagi A., Abe Y., Kaneko T., Kogen H. A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease. Bioorg. Med. Chem. 2003, 11:4389-4415.
34. Sterling J., Herzig Y., Goren T., Finkelstein N., Lerner D., Goldenberg W., Miskolczi I., Molnar S., Rantal F., Tamas T., Toth G., Zagyva A., Zekany A., Lavian G., Gross A., Friedman R., Razin M., Huang W., Krais B., Chorev M., Youdim M.B., Weinstock M. Novel dual inhibitors of AchE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease. J. Med. Chem. 2002, 45:5260-5270.
35. Sagi Y., Drigues N., Youdim M.B. The neurochemical and behavioral effects of the novel cholinesterase-monoamine oxidase inhibitor, ladostigil, in response to l-dopa and l-tryptophan, in rats. Br. J. Pharmacol. 2005, 146:543-552.
36. Henke B. Peroxisome proliferator-activated receptor α/γ dual agonists for the treatment of type 2 diabetes. J. Med. Chem. 2004, 47:4118-4127.
37. Xu Y., Rito C.J., Etgen G.J., Ardecky R.J., Bean S.J., Bensch W.R., Bosley J.R., Broderick C.L., Brooks D.A., Dominianni S.J., Hahn P.J., Dale S.L., Mais D.E., Montrose-Rafizadeh C., Ogilvie K.M., Oldham B.A., Peters M., Rungta D.K., Shuker A.J., Stephenson G.A., Tripp A.E., Wilson S.B., Winneroski L.L., Zink R., Kauffman R.K., McCarthy J.R. Design and Synthesis of α-aryloxy-α-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor α/γ agonists. J. Med. Chem. 2004, 47:2422-2425.
38. Lackey K.E. Lessons from the drug discovery of lapatinib, a dual ErbB1/2 tyrosine kinase inhibitor. Curr. Top. Med. Chem. 2006, 6:435-460.
39. Daub H., Specht K., Ullrich A. Strategies to overcome resistance to targeted protein kinase inhibitors. Nat. Rev. Drug Discov. 2004, 12:1001-1010.
40. Boschelli D., Wang Y., Johnson S., Wu B., Ye F., Sosa A., Golas J., Boschelli F. 7-Alkoxy-4-phenylamino-3-quinolinecarbonitriles as dual inhibitors of Src and Abl kinases. J. Med. Chem. 2004, 47:1599-1601.
41. Sun L., Liang C., Shirazian S., Zhou Y., Miller T., Cui J., Fukuda J.Y., Chu J.-Y., Nematalla A., Wang X., Chen H., Sistla A., Luu T.C., Tang F., Wei J., Tang C. Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-p yrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J. Med. Chem. 2003, 46:1116-1119.
42. Becknell N.B., Zulli A.L., Angeles T.S., Yang S., Albom M.S., Aimone L.D., Robinson C., Chang H., Hudkin R.L. Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors. Bioorg. Med. Chem. Lett. 2006, 16:5368-5372.
43. Vane, J. R. Nat. New Biol. 1971, 232-235.
44. Dannhard, G., Kiefer, W. Cyclooxigenase inhibitors-current status and future prospects. Eur. J. Med. Chem. 2001, 36, 109-126.
45. Fosslien E. Adverse effects of nonsteroidal antiinflammatory drugs on the gastrointestinal system. Ann. Clin. Lab. Sci. 1998, 28:67-81.
46. Weber A., Casini A., Heine A., Kuhn D., Supuran C.T., Scozzafava A., Klebe G. Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition. J. Med. Chem. 2004, 46:550-557.
47. Goossens L., Pommery N. Henichart, COX-2/5-LOX. Dual acting anti-inflammatory drugs in cancer chemotherapy. Curr. Top. Med. Chem. 2007, 7:283-296.
48. Barbey S., Goossens L., Taverne T., Cornet J., Choesmel V., Rouaud C., Gimeno G., Yannic-Arnoult S., Michaux C., Charlier C., Houssin R., Henichart J.P. Synthesis and activity of a new methoxytetrahydropyran derivative as dual cyclooxygenase-2/5-lipoxygenase inhibitor. Bioorg. Med. Chem. Lett. 2002, 12:779-782.
49. Di Napoli M.F., Papa F. NCX-4016 NicOX. Curr. Opin. Invest. Drugs 2003, 4:1126-1139.
50. Lolli M.L., Cena C., Medana C., Lazzarato L., Morini G., Coruzzi G., Manarini S., Fruttero R., Gasco A. A new class of Ibuprofen derivatives with reduced gastrotoxicity. J. Med. Chem. 2001, 44:3463-3468.
51. Kato K., Ohkawa S., Terao S., Terashita Z.I., Nishikava K. Thromboxane synthetase inhibitors (TXSI). Design, synthesis, and evaluation of a novel series of omega-pyridylalkenoic acids. J. Med. Chem. 1985, 28:287-294.
52. Soyka R., Heckel A., Nickl J., Eisert W., Muller T.H., Weisenberger H. 6,6-Disubstituted hex-5-enoic acid derivatives as combined thromboxane A2 receptor and synthetase inhibitors. J. Med. Chem. 1994, 37:26-39.
53. Gengo P.J., Pettit H.O., O'Neill S.J., Wei K., McNutt R., Bishop M.J., Chang K.-J. DPI-3290 [(+)-3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-h ydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. Mixed opioid agonist with potent antinociceptive activity. J. Pharmacol. Exp. Ther. 2003, 307:1221-1226.
54. Ananthan S., KezarIII H.S., Carter R.L., Saini S.K., Rice K.C., Wells J.L., Davis P., Xu H., Dersch C.M., Bilsky E.J., Porreca F., Rothman R.B. Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido-and pyrimidomorphinans. J. Med. Chem. 1999, 42:3527-3538.
55. 2-imidazoline receptors: synthesis and pharmacological screening. Bioorg. Med. Chem. 2002, 10:1009-1018.
56. 2-imidazoline binding sites. Bioorg. Med. Chem. Lett. 2004, 14:491-493.
57. Stahl S.M. Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression. Biol. Psychiatry 2002, 52:1166-1174.
58. Bymaster F.P., Beedle E.E., Findlay J., Gallagher P.T., Krushinski J.H., Mitchell S., Robertson D.W., Thompson D.C., Wallace L., Wong D.T. Duloxetine (Cymbalta TM), as dual inhibitor of serotonin and norepinephrine reuptake. Bioorg. Med. Chem. Lett. 2003, 13:4477-4480.
59. Nyberg S., Eriksson B., Oxenstierna G., Halldin C., Farde L. Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT(2A) receptor occupancy in schizophrenic patients. Am. J. Psychiatry 1999, 156:869-875.
60. 2-adrenoreceptor agonists for the treatment of airway diseases. 1. Discovery and biological evaluation of some 7-(2-aminoethyl)-4-hydroxybenzothiazol-2(3H)-one analogues. J. Med. Chem. 1998, 41:4915-4917.
61. Atkinson P., Bromidge S., Duxon M., Laramie M., Gaster L., Hadley M., Hammond B., Johnson C., Middlemiss D., North S., Price G., Rami H., Riley J., Scott C., Shaw T., Starr K., Stemp G., Thewlis K., Thomas D., Thompson M., Vong A., Watson J. 3,4-Dihydro-2H-benzoxazinones are 5-HT1A receptor antagonists with potent 5-HT reuptake inhibitory activity. Bioorg. Med. Chem. Lett. 2005, 15:737-741.
62. Meltzer H.Y. Illuminating the molecular basis for some antipsychotic drug-induced metabolic burden. Proc. Natl. Acad. Sci. USA 2007, 104:3019-3020.
63. Fabian M.A., Biggs W.H., Treiber D.K., Atteridge C.E., Azimioara M.D., Benedetti M.G., Carter T.A., Ciceri P., Edeen P.T., Floyd M., Ford J.M., Galvin M., Gerlach J.L., Grotzfeld R.M., Herrgard S., Insko D.E., Insko M.A., Lai A.G., Lélias J.M., Mehta S.A., Milanov Z.V., Velasco A.M., Wodicka L.M., Patel H.K., Zarrinkar P.P., Lockhart D.J. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 2005, 23:329-336.
64. Roskoski R. Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem. Biophys. Res. Commun. 2007, 356:323-328.
65. Force T., Krause D.S., van Etten R.A. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat. Rev. Cancer 2007, 7:332-344.
66. Dinges J., Albert D.H., Arnold L.D., Ashworth K.L., Akritopoulou-Zanze I., Bousquet P.F., Bouska J.J., Cunha G.A., Davidsen S.K., Diaz G.J., Djuric S.W., Gasiecki A.F., Gintant G.A., Gracias V.J., Harris C.M., Houseman K.A., Hutchins C.W., Johnson E.F., Li H., Marcotte P.A., Martin R.L., Michaelides M.R., Nyein M., Sowin T.J., Su Z., Tapang P.H., Xia Z., Zhang H.Q. 1,4-Dihydroindeno[1,2-c]pyrazoles with acetylenic side chains as novel and potent multitargeted receptor tyrosine kinase inhibitors with low affinity for the hERG Ion channel. J. Med. Chem. 2007, 50:2011-2029.
67. Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J. Experi-mental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 1997, 23:3-25.
68. Vieth M., Siegel M.G., Higgs R.E., Watson I.A., Robertson D.H., Savin K.A., Durst G.L., Hipskind P.A. Characteristic physical properties and structural fragments of marketed oral drugs. J. Med. Chem. 2004, 47:224-232.
69. Morphy J.R. The influence of target family and functional activity on the physicochemical properties of pre-clinical compounds. J. Med. Chem. 2006, 49:2969-2978.
70. Morphy J.R., Rankovic Z. The physicochemical challenges of designing multiple ligands. J. Med. Chem. 2006, 49:4961-4970.
71. Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J. Experi-mental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 1997, 23:3-25.
72. Veber D.F., Johnson S.R., Cheng H.Y., Smith B.R., Ward K.W., Kopple K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002, 45:2615-2623.
73. 2 and gastrin receptor antagonists. Bioorg. Med. Chem. Lett. 1996, 6:1427-1430.
74. Portoghese P.S. From models to molecules: opioid receptor dimers, bivalent ligands, and selective opioid receptor probes. J. Med. Chem. 2001, 44:2259-2269.
75. Daniels D.J., Kulkarni A., Xie Z., Bhushan R.G., Portoghese P.S. A bivalent ligand (KDAN-18) containing δ-antagonist and κ-agonist pharmacophores bridges δ2 and κ1 opioid receptor phenotypes. J. Med. Chem. 2005, 48:1713-1716.
76. Buijsman R.C., Basten J.E., van Dinther T.G., van der Marel G.A., van Boeckel C.A., van Boom J.H. Design and synthesis of a novel synthetic NAPAP-pentasaccharide conjugate displaying a dual antithrombotic action. Bioorg. Med. Chem. Lett. 1999, 9:2013-2018.
77. Morphy R., Rankovic Z. Fragments, network biology and designing multiple ligands. Drug Discov. Today 2007, 12:156-160.