The medicinal chemist's toolbox: An analysis of reactions used in the pursuit of drug candidates

Journal of Medicinal Chemistry

Volumn 54, Issue 10, 2011, Pages 3451-3479

  Roughley, Stephen D ^a   Jordan, Allan M ^b  

^a Vernalis PLC   (United Kingdom)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

NEW DRUG;

ACYLATION; ALKYLATION; ARYLATION; CHEMICAL REACTION; DEPROTECTION REACTION; DRUG MANUFACTURE; DRUG SCREENING; HALOGENATION; NITRATION; OLEFINATION; OXIDATION; PUBLICATION; REACTION ANALYSIS; REVIEW; SCIENTIFIC LITERATURE; SULFONATION; SYNTHESIS;

CHEMISTRY, PHARMACEUTICAL; DATABASES, FACTUAL; DRUG DESIGN; MODELS, CHEMICAL; PHARMACEUTICAL PREPARATIONS; TECHNOLOGY, PHARMACEUTICAL;

EID: 79957698619     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200187y     Document Type: Review

References (164)

1. Jordan, A. M.; Roughley, S. D. Drug discovery chemistry: a primer for the non-specialist Drug Discovery Today 2009, 14, 731-744
2. Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Analysis of the reactions used for the preparation of drug candidate molecules Org. Biomol. Chem. 2006, 2337-2347 (Pubitemid 43882754)
3. Thomson Reuters ISI impact factors for 2008 were retrieved from the journal Internet homepages (JMC, http://pubs.acs.org/journal/jmcmar; BMC, http://journals.elsevier.com/09680896/bioorganic-and-medicinal-chemistry/; BMCL, http://www.elsevier.com/wps/find/journaldescription.cws-home/972/ description#description) at the time of data compilation.
4. Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J. F. Factors determining the selection of organic reactions by medicinal chemists and the use of these reactions in arrays (small focussed libraries) Angew. Chem., Int. Ed. 2010, 49, 2-12
5. CAS SciFinder. http://www.cas.org/products/scifindr/index.html (accessed Feb 7, 2011).
6. Reaxys Elsevier Beilstein Database. http://www.reaxys.com/info (accessed Feb 7, 2011).
7. Lipinksi, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug Delivery Rev. 2001, 46, 3-26 (Pubitemid 33653411)
8. Lipinksi, C. A. Lead- and drug-like compounds: the rule-of-five revolution Drug Discovery Today: Technol. 2004, 1, 337-341
9. log P is calculated in RDKit using the atomic contribution algorithm of Crippen: Wildman, S. A.; Crippen, G. M. Prediction of physicochemical parameters by atomic contributions J. Chem. Inf. Comput. Sci. 1999, 39, 868-873
10. 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 (Pubitemid 34595232)
11. Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties J. Med. Chem. 2000, 43, 3714-3717
12. Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: increasing saturation as an approach to improving clinical success J. Med. Chem. 2009, 52, 6752-6756
13. Python. http://www.python.org (accessed Mar 19, 2010).
14. RDKit: Open-Source Cheminformatics. http://www.rdkit.org (accessed Apr 25, 2010).
15. SMARTS-A Language for Describing Molecular Patterns. http://www.daylight. com/dayhtml/doc/theory/index.pdf (accessed Jan 20, 2011).
16. Schomburg, K.; Ehrlich, H. C.; Stierand, K.; Rarey, M. From structure diagrams to visual chemical patterns J. Chem. Inf. Model. 2010, 50, 1529-1535
17. SMARTSViewer. http://smartsview.zbh.uni-hamburg.de/ (accessed Jan 20, 2011).
18. Ritchie, T. J.; Macdonald, S. J. F. The impact of aromatic ring count on compound developability: Are too many aromatic rings a liability in drug design? Drug Discovery Today 2009, 14, 1011-1020
19. Berthold, M. R.; Cebron, N.; Dill, F.; Gabriel, T. R.; Kötter, T.; Meinl, T.; Ohl, P.; Sieb, C.; Thiel, K.; Wiswedel, B. KNIME: The Konstanz Information Miner. In Studies in Classification, Data Analysis, and Knowledge Organization; Springer: Berlin, Germany, 2007.
20. KNIME: The Konstanz Information Miner. http://www.knime.org (accessed Jan 20, 2011).
21. Baran, P. S.; Maimone, T. J.; Richter, J. M. Total synthesis of marine natural products without using protecting groups Nature 2007, 446, 404-408 (Pubitemid 46476780)
22. Gaich, T.; Baran, P. S. Aiming for the ideal synthesis J. Org. Chem. 2010, 75, 4657-4673
23. Shenvi, R. A.; O?Malley, D. P.; Baran, P. S. Chemoselectivity: the mother of invention in total synthesis Acc. Chem. Res. 2009, 42, 530-541
24. Young, I. S.; Baran, P. S. Protecting-group-free synthesis as an opportunity for invention Nat. Chem. 2009, 1, 193-205
25. Ertl, P.; Jelfs, S.; Mühlbacher, J.; Schuffenhauer, A.; Selzer, P. Quest for the rings. In silico exploration of ring universe to identify novel bioactive heteroaromatic scaffolds J. Med. Chem. 2006, 49, 4568-4573 (Pubitemid 44162682)
26. Bemis, G. W.; Murcko, M. A. The properties of known drugs. 1. Molecular frameworks J. Med. Chem. 1996, 39, 2887-2893 (Pubitemid 26251026)
27. Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. Heteroaromatic rings of the future J. Med. Chem. 2009, 52, 2952-2963
28. Abdel-Magid, A. F.; Mehrman, S. J. A review on the use of sodium triacetoxyborohydride in the reductive amination of ketones and aldehydes Org. Process Res. Dev 2006, 10, 971-1031 (Pubitemid 44594592)
29. Baxter, E. W.; Reitz, A. B. Reductive aminations of carbonyl compounds with borohydride and borane reducing agents Org. React. 2002, 59, 1-714
30. Makosza, M. Nucleophilic substitution of hydrogen in electron-deficient arenes-a general process of great practical value Chem. Soc. Rev. 2010, 39, 2855-2868
31. Van der Plas, H. C. The SN(ANRORC) mechanism: a new mechanism for nucleophilic substitution Acc. Chem. Res. 1978, 11, 462-468
32. RN1 Reaction Org. React. 2004, 1-271
33. Hartwig, J. F. Carbon-heteroatom bond-forming reductive eliminations of amines, ethers, and sulfides Acc. Chem. Res. 1998, 31, 852-860 (Pubitemid 128473636)
34. Hartwig, J. F. Transition metal catalyzed synthesis of arylamines and aryl ethers from aryl halides and triflates: scope and mechanism Angew. Chem., Int. Ed. 1998, 37, 2046-2-67
35. Hartwig, J. F. Carbon-heteroatom bond formation catalysed by organometallic complexes Nature 2008, 455, 314-322
36. Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination Angew. Chem., Int. Ed. 2008, 47, 6338-6361
37. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Rational development of practical catalysts for aromatic carbon-nitrogen bond formation Acc. Chem. Res. 1998, 31, 805-818 (Pubitemid 128473631)
38. Wolfe, J. P.; Buchwald, S. L. Palladium-Catalyzed Amination of Aryl Halides and Aryl Triflates: N -Hexyl-2-methyl-4-methoxyaniline and N -Methyl- N -(4-chlorophenyl)aniline. Organic Syntheses; Wiley & Sons: New York, 2004; Collect. Vol. 10, p 423.
39. Yang, B. H.; Buchwald, S. L. Palladium-catalyzed amination of aryl halides and sulfonates J. Organomet. Chem. 1999, 576, 125-146 (Pubitemid 129595972)
40. Corbet, J.-P.; Mignani, G. Selected patented cross-coupling reaction technologies Chem. Rev. 2006, 106, 2651-2710 (Pubitemid 44207754)
41. Hughes, D. L. The Mitsunobu reaction Org. React. 1992, 42, 335-656
42. Mitsunobu, O. The use of diethyl azodicarboxylate and triphenylphoshine in synthesis and transformation of natural products Synthesis 1981, 1-28
43. Han, S. Y.; Kim, Y.-A. Recent development of peptide couping reagents in organic synthesis Tetrahedron 2004, 60, 2447-2467 (Pubitemid 38249561)
44. Montalbetti, C. A. G. N.; Falque, V. Amide bond formation and peptide coupling Tetrahedron 2005, 61, 10827-10852 (Pubitemid 41447509)
45. Ettmayer, P.; Amidon, G. L.; Clement, B.; Testa, B. Lessons learned from marketed and investigational prodrugs J. Med. Chem. 2004, 47, 2393-2404 (Pubitemid 38580074)
46. Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen, T.; Savolainen, J. Prodrugs: design and clinical applications Nat. Rev. Drug Discovery 2008, 7, 255-270 (Pubitemid 351324639)
47. Accelrys (formerly Symyx) Available Chemicals Directory, version 2010.08. http://accelrys.com/products/databases/sourcing/available-chemicals-directory. html (accessed Feb 2, 2011).
48. Kotha, S. Recent applications of the Suzuki-Miyaura cross-coupling reaction in organic synthesis Tetrahedron 2002, 58, 9633-9695 (Pubitemid 35356429)
49. Miyaura, N.; Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds Chem. Rev. 1995, 95, 2457-2483
50. Stanforth, S. P. Catalytic cross-coupling reactions in biaryl synthesis Tetrahedron 1998, 54, 263-303 (Pubitemid 28015445)
51. Many boronic acids and related derivatives are stable solids that can be easily weighed and stored, often for periods of years without serious degradation, in contrast with the organozinc and Grignard reagents of the Negishi and Kumada couplings.
52. Compare with the Stille reaction of organostannanes, which are highly toxic, often significantly volatile, and generate toxic tin-based byproducts that can be troublesome to separate from the desired product and represent a serious environmental hazard in their storage and disposal.
53. Negishi, E.-I. A genealogy of Pd-catalyzed cross-coupling J. Organomet. Chem. 2002, 653, 34-40 (Pubitemid 34594495)
54. Negishi, E.-I. Palladium-catalyzed alkynylation Chem. Rev. 2003, 103, 1979-2017
55. 2-carbon halides J. Organomet. Chem. 2002, 653, 46-49 (Pubitemid 34594497)
56. Brammertz, A.; Augthun, M. Toxicity of palladium in animals Wiss. Umwelt 1992, 285-289
57. Iavicoli, I.; Bocca, B.; Fontana, L.; Caimi, S.; Bergamaschi, A.; Alimonti, A. Distribution and elimination of palladium in rats after 90-day oral administration Toxicol. Ind. Health 2010, 26, 183-189
58. Kielhorn, J.; Melber, C.; Keller, D.; Mangelsdorf, I. Palladium, a review of exposure and effects to human health Int. J. Hyg. Environ. Health 2002, 205, 417-432 (Pubitemid 35265097)
59. Nahm, S.; Weinreb, S. M. N -Methoxy- N -methylamides as effective acylating agents Tetrahedron Lett. 1981, 22, 3815-3818
60. Labeeuw, O.; Phansavath, P.; Genet, J.-P. Synthesis of modified Weinreb amides: N-tert -butoxy- N -methylamides as effective acylating agents Tetrahedron Lett. 2004, 45, 7107-7110 (Pubitemid 39178574)
61. Davies, S. G.; Goodwin, C. J.; Hepworth, D.; Roberts, P. M.; Thomson, J. E. On the origins of diastereoselectivity in the alkylation of enolates derived from N -1-(1′-naphthyl)ethyl- O-tert -butylhydroxamates: chiral Weinreb amide equivalents J. Org. Chem. 2010, 75, 1214-1227
62. Boutagy, J.; Thomas, R. Olefin synthesis with organic phosphonate carbanions Chem. Rev. 1974, 74, 87-99
63. Maercker, A. The Wittig reaction Org. React. 1965, 14, 270-490
64. Maryanoff, B. E.; Reitz, A. B. The Wittig olefination reaction and modifications involving phosphoryl-stabilised carbanions. Stereochemistry, mechanism and selected synthetic aspects Chem. Rev. 1989, 89, 863-927
65. Cowden, C. J.; Paterson, I. Asymmetric aldol reactions using boron Org. React. 1997, 51, 1-200
66. Guillena, G.; Najera, C.; Ramon, D. J. Enantioselective direct aldol reaction: the blossoming of modern organocatalysis Tetrahedron: Asymmetry 2007, 18, 2249-2293 (Pubitemid 47576631)
67. Mukaiyama, T. The directed aldol reaction Org. React. 1982, 203-331
68. Palomo, C.; Oiarbide, M.; Garcia, J. M. The aldol addition reaction: and old transformation at constant rebirth Chem.-Eur. J. 2002, 8, 36-44 (Pubitemid 34087365)
69. Schetter, B.; Mahrwald, R. Modern aldol methods for the total synthesis of polyketides Angew. Chem., Int. Ed. 2006, 45, 7506-7525 (Pubitemid 44851671)
70. Trost, B. M.; Brindle, C. S. The direct catalytic asymmetric aldol reaction Chem. Soc. Rev. 2010, 39, 1600-1632
71. Walters, I.; Austin, C.; Austin, R.; Bonnert, R.; Cage, P.; Christie, M.; Ebden, M.; Gardiner, S.; Grahames, C.; Hill, S.; Hunt, F.; Jewell, R.; Lewis, S.; Martin, I.; Nicholls, D.; Robinson, D. Evaluation of a series of bicyclic CXCR2 antagonists Bioorg. Med. Chem. Lett. 2008, 18, 798-803
72. Bardelle, C.; Coleman, T.; Cross, D.; Davenport, S.; Kettle, J. G.; Ko, E. J.; Leach, A. G.; Mortlock, A.; Read, J.; Roberts, N. J.; Robins, P.; Williams, E. J. Inhibitors of the tyrosine kinase EphB4. Part 2. Structure-based discovery and optimization of 3,5-bis substituted anilinopyrimidines Bioorg. Med. Chem. Lett. 2008, 18, 5717-5721
73. Deaton, D. N.; Gao, E. N.; Graham, K. P.; Gross, J. W.; Miller, A. B.; Strelow, J. M. Thiol-based angiotensin-converting enzyme 2 inhibitors: P1 modifications for the exploration of the S1 subsite Bioorg. Med. Chem. Lett. 2008, 18, 732-737
74. Jiang, C.; Chang, J.-Y. Unfolding and breakdown of insulin in the presence of endogenous thiols FEBS Lett. 2005, 579, 3927-3931 (Pubitemid 40961890)
75. Heck, R. F. Palladium-catalyzed vinylation of organic halides Org. React. 1982, 27, 345-390
76. Wan, Z.; Yan, H.; Hall, R. F.; Lin, X.; Livia, S.; Respondek, T.; Widdowson, K. L.; Zhu, C.; Callahan, J. F. Design and development of arrayable syntheses to accelerate SAR studies of pyridopyrimidinone and pyrimidopyrimidinone Tetrahedron Lett. 2009, 50, 370-372
77. Yan, H.; Boehm, J. C.; Jin, Q.; Kasparec, J.; Li, H.; Zhu, C.; Widdowson, K. L.; Callahan, J. F.; Wan, Z. An improved and highly convergent synthesis of 4-substituted-pyrido[2.3- d ]pyrimidin-7-ones Tetrahedron Lett. 2007, 48, 1205-1207 (Pubitemid 46097041)
78. Burns, N. Z.; Baran, P. S.; Hoffman, R. W. Redox economy in organic synthesis Angew. Chem., Int. Ed. 2009, 48, 2854-2867
79. Baldwin, I.; Bamborough, P.; Haslam, C. G.; Hunjan, S. S.; Longstaff, T.; Mooney, C. J.; Patel, S.; Quinn, J.; Somers, D. O. Kinase array design, back to front: biaryl amides Bioorg. Med. Chem. Lett. 2008, 18, 5285-5289
80. The authors have heard various figures mentioned in conference presentations and other discussions but never with supporting data or citations.
81. Ritchie, T. J.; Macdonald, S. J. F.; Young, R. J.; Pickett, S. D. The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types Drug Discovery Today 2011, 16, 164-171
82. Jaeckel, H.; Klein, W. Prediction of mammalian toxicity by quantitative structure-activity relationships: aliphatic amines and anilines Quant. Struct.-Act. Relat. 1991, 10, 198-204
83. Karki, S. B.; Dinnocenzo, J. P.; Jones, J. P.; Korzekwa, K. R. Mechanism of oxidative amine dealkylation of substituted N, N -dimethylanilines by cytochrome P-450: application of isotope effect profiles J. Am. Chem. Soc. 1995, 117, 3657-3664
84. Zok, S.; Görge, G.; Kalsch, W.; Nagel, R. Bioconcentration, metabolism and toxicity of substituted anilines in the zebrafish (Brachydanio rerio) Sci. Total Environ. 1991, 109-110, 411-421
85. Ghose, A. K.; Herbertz, T.; Salvino, J. M.; Mallamo, J. P. Knowledge-based chemoinformatic approaches to drug discovery Drug Discovery Today 2006, 11, 1107-1114 (Pubitemid 44803112)
86. Akritopoulou-Zanze, I.; Hajduk, P. J. Kinase-targeted libraries: the design and synthesis of novel, potent, and selective kinase inhibitors Drug Discovery Today 2009, 14, 291-297
87. Brown, A.; Brown, L.; Brown, T. B.; Calabrese, A.; Ellis, D.; Puhalo, N.; Smith, C. R.; Wallace, O.; Watson, L. Triazole oxytocin antagonists: identification of aryl ether replacements for a biaryl substituent Bioorg. Med. Chem. Lett. 2008, 18, 5242-5244
88. Patel, S. D.; Habeski, W. M.; Min, H.; Zhang, J.; Roof, R.; Snyder, B.; Bora, G.; Campbell, B.; Li, C.; Hidayetoglu, D.; Johnson, D. S.; Chaudhry, A.; Charlton, M. E.; Kablaoui, N. M. Identification and SAR around N -{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl} -2-phenoxy-nicotinamide, a selective α2C adrenergic receptor antagonist Bioorg. Med. Chem. Lett. 2008, 18, 5689-5693
89. Fish, P. V.; Deur, C.; Gan, X.; Greene, K.; Hoople, D.; MacKenny, M.; Para, K. S.; Reeves, K.; Ryckmans, T.; Stiff, C.; Stobie, A.; Wakenhut, F.; Whitlock, G. A. Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition Bioorg. Med. Chem. Lett. 2008, 18, 2562-2566 (Pubitemid 351503895)
90. Xu, W.; Gray, D. L.; Glase, S. A.; Barta, N. S. Design and synthesis of reboxetine analogs morpholine derivatives as selective norepinephrine reuptake inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 5550-5553
91. Whitlock, G. A.; Blagg, J.; Fish, P. V. 1-(2-Phenoxyphenyl)methanamines: SAR for dual serotonin/noradrenaline reuptake inhibition, metabolic stability and hERG affinity Bioorg. Med. Chem. Lett. 2008, 18, 596-599
92. Middleton, D. S.; Andrews, M.; Glossop, P.; Gymer, G.; Hepworth, D.; Jessiman, A.; Johnson, P. S.; MacKenny, M.; Pitcher, M. J.; Rooker, T.; Stobie, A.; Tang, K.; Morgan, P. Designing rapid onset selective serotonin re-uptake inhibitors. 2: Structure-activity relationships of substituted (aryl)benzylamines Bioorg. Med. Chem. Lett. 2008, 18, 4018-4021
93. Mente, S.; Gallaschun, R.; Schmidt, A.; Lebel, L.; Vanase-Frawley, M.; Fliri, A. Quantitative structure-activity relationship of phenoxyphenyl- methanamine compounds with 5HT2A, SERT and hERG activities Bioorg. Med. Chem. Lett. 2008, 18, 6088-6092
94. Fish, P. V.; Ryckmans, T.; Stobie, A.; Wakenhut, F. [4-(Phenoxy)pyridin- 3-yl]methylamines: a new class of selective noradrenaline reuptake inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 1795-1798 (Pubitemid 351380914)
95. Whitlock, G. A.; Fish, P. V.; Fary, M. J.; Stobie, A.; Wakenhut, F. Pyridyl-phenyl ether monoamine reuptake inhibitors: impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity Bioorg. Med. Chem. Lett. 2008, 18, 2896-2899 (Pubitemid 351608879)
96. Pfefferkorn, J. A.; Choi, C.; Winters, T.; Kennedy, R.; Chi, L.; Perrin, L. A.; Lu, G.; Ping, Y.-W.; McClanahan, T.; Schroeder, R.; Leininger, M. T.; Geyer, A.; Schefzick, S.; Atherton, J. P2Y1 receptor antagonists as novel antithrombotic agents Bioorg. Med. Chem. Lett. 2008, 18, 3338-3343 (Pubitemid 351721005)
97. Chen, Y. L.; Braselton, J.; Forman, J.; Gallaschun, R.; Mansbach, R.; Schmidt, A. W.; Seeger, T. F.; Sprouse, J. S.; Tingley, F. D.; Winston, E.; Schulz, D. W. Synthesis and SAR of 2-aryloxy-4-alkoxy-pyridines as potent orally active corticotropin-releasing factor 1 receptor antagonists J. Med. Chem. 2008, 51, 1377-1384 (Pubitemid 351480398)
98. Barlaam, B.; Ballard, P.; Bradbury, R. H.; Ducray, R.; Germaine, H.; Hickinson, D. M.; Hudson, K.; Kettle, J. G.; Klinowska, T.; Magnien, F.; Ogilvie, D. J.; Olivier, A.; Pearson, S. E.; Scott, J. S.; Suleman, A.; Trigwell, C. B.; Vautier, M.; Whittaker, R. D.; Wood, R. A new series of neutral 5-substituted 4-anilinoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase Bioorg. Med. Chem. Lett. 2008, 18, 674-678
99. Fang, J.; Akwabi-Ameyaw, A.; Britton, J. E.; Katamreddy, S. R.; Navas, F.; Miller, A. B.; Williams, S. P.; Gray, D. W.; Orband-Miller, L. A. Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands Bioorg. Med. Chem. Lett. 2008, 18, 5075-5077
100. Micheli, F.; Bonanomi, G.; Braggio, S.; Capelli, A. M.; Celestini, P.; Damiani, F.; Di Fabio, R.; Donati, D.; Gagliardi, S.; Gentile, G.; Hamprecht, D.; Petrone, M.; Radaelli, S.; Tedesco, G.; Terreni, S.; Worby, A.; Heidbreder, C. New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part one: [h]-fused tricyclic systems Bioorg. Med. Chem. Lett. 2008, 18, 901-907 (Pubitemid 351187883)
101. Micheli, F.; Bonanomi, G.; Braggio, S.; Capelli, A. M.; Damiani, F.; Di Fabio, R.; Donati, D.; Gentile, G.; Hamprecht, D.; Perini, O.; Petrone, M.; Tedesco, G.; Terreni, S.; Worby, A.; Heidbreder, C. New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part 2: [g]-Fused and hetero-fused systems Bioorg. Med. Chem. Lett. 2008, 18, 908-912 (Pubitemid 351179359)
102. Young, R. J.; Borthwick, A. D.; Brown, D.; Burns-Kurtis, C. L.; Campbell, M.; Chan, C.; Charbaut, M.; Chung, C.-W.; Convery, M. A.; Kelly, H. A.; King, N. P.; Kleanthous, S.; Mason, A. M.; Pateman, A. J.; Patikis, A. N.; Pinto, I. L.; Pollard, D. R.; Senger, S.; Shah, G. P.; Toomey, J. R.; Watson, N. S.; Weston, H. E. Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs Bioorg. Med. Chem. Lett. 2008, 18, 23-27
103. Young, R. J.; Borthwick, A. D.; Brown, D.; Burns-Kurtis, C. L.; Campbell, M.; Chan, C.; Charbaut, M.; Convery, M. A.; Diallo, H.; Hortense, E.; Irving, W. R.; Kelly, H. A.; King, N. P.; Kleanthous, S.; Mason, A. M.; Pateman, A. J.; Patikis, A. N.; Pinto, I. L.; Pollard, D. R.; Senger, S.; Shah, G. P.; Toomey, J. R.; Watson, N. S.; Weston, H. E.; Zhou, P. Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs Bioorg. Med. Chem. Lett. 2008, 18, 28-33
104. Walker, D. P.; Bi, C. F.; Kalgutkar, A. S.; Bauman, J. N.; Zhao, S. X.; Soglia, J. R.; Aspnes, G. E.; Kung, D. W.; Klug-McLeod, J.; Zawistoski, M. P.; McGlynn, M. A.; Oliver, R.; Dunn, M.; Li, J. C.; Richter, D. T.; Cooper, B. A.; Kath, J. C.; Hulford, C. A.; Autry, C. L.; Luzzio, M. J.; Ung, E. J.; Roberts, W. G.; Bonnette, P. C.; Buckbinder, L.; Mistry, A.; Griffor, M. C.; Han, S.; Guzman-Perez, A. Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation Bioorg. Med. Chem. Lett. 2008, 18, 6071-6077
105. Micale, N.; Colleoni, S.; Postorino, G.; Pellicanò, A.; Zappalà, M.; Lazzaro, J.; Diana, V.; Cagnotto, A.; Mennini, T.; Grasso, S. Structure-activity study of 2,3-benzodiazepin-4-ones noncompetitive AMPAR antagonists: identification of the 1-(4-amino-3-methylphenyl)-3,5-dihydro-7,8- ethylenedioxy-4 H -2,3-benzodiazepin-4-one as neuroprotective agent Bioorg. Med. Chem. 2008, 16, 2200-2211 (Pubitemid 351380956)
106. Tian, X.; Switzer, A. G.; Derose, S. A.; Mishra, R. K.; Solinsky, M. G.; Mumin, R. N.; Ebetino, F. H.; Jayasinghe, L. R.; Webster, M. E.; Colson, A. O.; Crossdoersen, D.; Pinney, B. B.; Farmer, J. A.; Dowty, M. E.; Obringer, C. M.; Cruze, C. A.; Burklow, M. L.; Suchanek, P. M.; Dong, L.; Dirr, M. K.; Sheldon, R. J.; Wos, J. A. Discovery of orally bioavailable 1,3,4-trisubstituted 2-oxopiperazine-based melanocortin-4 receptor agonists as potential antiobesity agents J. Med. Chem. 2008, 51, 6055-6066
107. Kazmierski, W. M.; Aquino, C.; Chauder, B. A.; Deanda, F.; Ferris, R.; Jones-Hertzog, D. K.; Kenakin, T.; Koble, C. S.; Watson, C.; Wheelan, P.; Yang, H.; Youngman, M. Discovery of bioavailable 4,4-disubstituted piperidines as potent ligands of the chemokine receptor 5 and inhibitors of the human immunodeficiency virus-1 J. Med. Chem. 2008, 51, 6538-6546
108. Liddle, J.; Allen, M. J.; Borthwick, A. D.; Brooks, D. P.; Davies, D. E.; Edwards, R. M.; Exall, A. M.; Hamlett, C.; Irving, W. R.; Mason, A. M.; McCafferty, G. P.; Nerozzi, F.; Peace, S.; Philp, J.; Pollard, D.; Pullen, M. A.; Shabbir, S. S.; Sollis, S. L.; Westfall, T. D.; Woollard, P. M.; Wu, C.; Hickey, D. M. B. The discovery of GSK221149A: a potent and selective oxytocin antagonist Bioorg. Med. Chem. Lett. 2008, 18, 90-94
109. Harriman, G. C.; Brewer, M.; Bennett, R.; Kuhn, C.; Bazin, M.; Larosa, G.; Skerker, P.; Cochran, N.; Gallant, D.; Baxter, D.; Picarella, D.; Jaffee, B.; Luly, J. R.; Briskin, M. J. Selective cell adhesion inhibitors: barbituric acid based α4β7-MAdCAM inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 2509-2512 (Pubitemid 351442876)
110. Clarke, B.; Demont, E.; Dingwall, C.; Dunsdon, R.; Faller, A.; Hawkins, J.; Hussain, I.; MacPherson, D.; Maile, G.; Matico, R.; Milner, P.; Mosley, J.; Naylor, A.; O?Brien, A.; Redshaw, S.; Riddell, D.; Rowland, P.; Soleil, V.; Smith, K. J.; Stanway, S.; Stemp, G.; Sweitzer, S.; Theobald, P.; Vesey, D.; Walter, D. S.; Ward, J.; Wayne, G. BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs) Bioorg. Med. Chem. Lett. 2008, 18, 1011-1016 (Pubitemid 351179341)
111. Clarke, B.; Demont, E.; Dingwall, C.; Dunsdon, R.; Faller, A.; Hawkins, J.; Hussain, I.; MacPherson, D.; Maile, G.; Matico, R.; Milner, P.; Mosley, J.; Naylor, A.; O?Brien, A.; Redshaw, S.; Riddell, D.; Rowland, P.; Soleil, V.; Smith, K. J.; Stanway, S.; Stemp, G.; Sweitzer, S.; Theobald, P.; Vesey, D.; Walter, D. S.; Ward, J.; Wayne, G. BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character Bioorg. Med. Chem. Lett. 2008, 18, 1017-1021 (Pubitemid 351179342)
112. Serafinowska, H. T.; Blaney, F. E.; Lovell, P. J.; Merlo, G. G.; Scott, C. M.; Smith, P. W.; Starr, K. R.; Watson, J. M. Novel 5-HT1A/1B/1D receptors antagonists with potent 5-HT reuptake inhibitory activity Bioorg. Med. Chem. Lett. 2008, 18, 5581-5585
113. Bromidge, S. M.; Bertani, B.; Borriello, M.; Faedo, S.; Gordon, L. J.; Granci, E.; Hill, M.; Marshall, H. R.; Stasi, L. P.; Zucchelli, V.; Merlo, G.; Vesentini, A.; Watson, J. M.; Zonzini, L. 6-[2-(4-Aryl-1-piperazinyl)ethyl]-2 H -1,4-benzoxazin-3(4 H)-ones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 5653-5656
114. With 23 heteroaromatic rings and benzene exemplified within the data set, even without the possibility of different fusion bond isomers, there are 24 ? - 24 = 576 possible ring types (comprising 64 6,6-fused, 256 5,5-fused, and 128 6,5-fused systems). Fusion isomers increase this figure dramatically (for example, the relatively symmetrical pyridine and pyrrole pairing can generate seven different fusion isomers).
115. Lewell, X. Q.; Jones, A. C.; Bruce, C. L.; Harper, G.; Jones, M. M.; Mclay, I. M.; Bradshaw, J. Drug rings database with Web interface. A tool for identifying alternative chemical rings in lead discovery programs J. Med. Chem. 2003, 46, 3257-3274 (Pubitemid 36842410)
116. Southall, N. T.; Ajay Kinase patent space visualisation using chemical replacements J. Med. Chem. 2006, 49, 2103-2109
117. Jin, J.; Wang, Y.; Shi, D.; Wang, F.; Davis, R. S.; Jin, Q.; Fu, W.; Foley, J. J.; Webb, E. F.; Dehaas, C. J.; Berlanga, M.; Burman, M.; Sarau, H. M.; Morrow, D. M.; Rao, P.; Kallal, L. A.; Moore, M. L.; Rivero, R. A.; Palovich, M.; Salmon, M.; Belmonte, K. E.; Busch-Petersen, J. Discovery of novel and long acting muscarinic acetylcholine receptor antagonists J. Med. Chem. 2008, 51, 4866-4869
118. Kung, P. P.; Funk, L.; Meng, J.; Collins, M.; Zhou, J. Z.; Johnson, M. C.; Ekker, A.; Wang, J.; Mehta, P.; Yin, M. J.; Rodgers, C.; Davies, J. F., II; Bayman, E.; Smeal, T.; Maegley, K. A.; Gehring, M. R. Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone Bioorg. Med. Chem. Lett. 2008, 18, 6273-6278
119. Deaton, D. N.; Graham, K. P.; Gross, J. W.; Miller, A. B. Thiol-based angiotensin-converting enzyme 2 inhibitors: P1′ modifications for the exploration of the S1′ subsite Bioorg. Med. Chem. Lett. 2008, 18, 1681-1687 (Pubitemid 351318237)
120. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in medicinal chemistry Chem. Soc. Rev. 2008, 37, 320-330
121. O?Hagan, D. Understanding organofluorine chemistry. An introduction to the C-F bond Chem. Soc. Rev. 2008, 37, 308-319
122. Hodgetts, K. J.; Combs, K. J.; Elder, A. M.; Harriman, G. C. The role of fluorine in the discovery and optimization of CNS agents: modulation of drug-like properties Annu. Rep. Med. Chem. 2010, 45, 429-448
123. Bissantz, C.; Kuhn, B.; Stahl, M. A medicinal chemist's guide to molecular interactions J. Med. Chem. 2010, 53, 5061-5084
124. 3: preparation of gem-difluoroalkenes and trifluoromethyl compounds Tetrahedron Lett. 2010, 51, 6150-6152
125. Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V. Development of fluorination methods using continuous-flow microreactors Tetrahedron 2009, 65, 6611-6625
126. Hagooly, Y.; Cohen, O.; Rozen, S. A general route for constructing difluoromethyl ethers Tetrahedron Lett. 2009, 50, 392-394
127. Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S. Halogen bonds in biological molecules Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 16789-16794 (Pubitemid 39601317)
128. Lu, Y.; Ting, S.; Wang, Y.; Yang, H.; Yan, X.; Luo, X.; Jiang, H.; Zhu, W. Halogen bonding: a novel interaction for rational drug design? J. Med. Chem. 2009, 52, 2854-2862
129. Zhou, P.; Lv, J.; Zou, J.; Tian, F.; Shang, Z. Halogen-water-hydrogen bridges in biomolecules J. Struct. Biol. 2010, 169, 172-182
130. Hernandes, M. Z.; Cavalcanti, S. M. T.; Moreira, D. R. M. Halogens atoms in the modern medicinal chemistry: hints for the drug design Curr. Drug. Targets 2010, 11, 303-314
131. O?Dowd, H.; Lewis, J. G.; Trias, J.; Asano, R.; Blais, J.; Lopez, S. L.; Park, C. K.; Wu, C.; Wang, W.; Gordeev, M. F. Novel antibacterial azetidine lincosamides Bioorg. Med. Chem. Lett. 2008, 18, 2645-2648 (Pubitemid 351503884)
132. Barrett, S. D.; Bridges, A. J.; Dudley, D. T.; Saltiel, A. R.; Fergus, J. H.; Flamme, C. M.; Delaney, A. M.; Kaufman, M.; LePage, S.; Leopold, W. R.; Przybranowski, S. A.; Sebolt-Leopold, J.; Van Becelaere, K.; Doherty, A. M.; Kennedy, R. M.; Marston, D.; Howard, W. A., Jr.; Smith, Y.; Warmus, J. S.; Tecle, H. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901 Bioorg. Med. Chem. Lett. 2008, 18, 6501-6504
133. Warmus, J. S.; Flamme, C.; Zhang, L. Y.; Barrett, S.; Bridges, A.; Chen, H.; Gowan, R.; Kaufman, M.; Sebolt-Leopold, J.; Leopold, W.; Merriman, R.; Ohren, J.; Pavlovsky, A.; Przybranowski, S.; Tecle, H.; Valik, H.; Whitehead, C.; Zhang, E. 2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles- O -Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase) Bioorg. Med. Chem. Lett. 2008, 18, 6171-6174
134. Protein Data Bank (PDB). http://www.rcsb.org/ (accessed Feb 13, 2011).
135. Tecle, H.; Shao, J.; Li, Y.; Kothe, M.; Kazmirski, S.; Penzotti, J.; Ding, Y. H.; Ohren, J.; Moshinsky, D.; Coli, R.; Jhawar, N.; Bora, E.; Jacques-O?Hagan, S.; Wu, J. Beyond the MEK-pocket: Can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK? Bioorg. Med. Chem. Lett. 2009, 19, 226-229
136. Note that this figure, being almost twice the total number of reactions (7315) in our data set, reflects the general approach of building a common scaffold, which is subsequently used to prepare multiple analogues.
137. Manual inspection revealed a further 339 compounds containing 1 (315 compounds) or 2 (34 compounds) undefined or only partially defined stereocenters, a total of 383 additional stereocenters. Many of these were the result of the addition of simple substituents (Me, OH, OMe, etc.) to prochiral centers or from a small number of scaffolds with a racemic center. Presumably, the vast majority of these were not deemed of sufficient interest to invest in asymmetric synthesis or resolution.
138. While Lipinski's rules relate to oral absorption, in most cases no intended dose route was identified in many of the papers examined. We assume for the purposes of this analysis that oral dosing would be the desired "gold standard".
139. Lipinski notes in ref 7 the importance of their goal of generating simple parameters that are easily accessible to medicinal chemists using their pattern recognition skills.
140. Giaginis, C.; Zira, A.; Theocharis, S.; Tsantili-Kakoulidou, A. Simple physicochemical properties as effective filters for risk estimation of drug transport across the human placental barrier Epitheor. Klin. Farmakol. Farmakokinet., Int. Ed. 2008, 22, 146-148 (Pubitemid 351831235)
141. Choy, Y.-B.; Prausnitz, M. R. The rule of five for non-oral routes of drug delivery: ophthalmic, inhalation and transdermal Pharm. Res. 2011, 28, 943-948
142. Lewis, D. F. V.; Jacobs, M. N.; Dickins, M. Compound lipophilicity for substrate binding to human P450s in drug metabolism Drug Discovery Today 2004, 9, 530-537 (Pubitemid 38739334)
143. Waring, M. J.; Johnstone, C. A quantitative assessment of hERG liability as a function of lipophilicity Bioorg. Med. Chem. Lett. 2007, 17, 1759-1764
144. Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; DeCrescenzo, G. A.; Devraj, R. V.; Elsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Giles, R. W.; Greene, N.; Huang, E.; Krieger-Burke, T.; Loesel, J.; Wager, T.; Whiteley, L.; Zhang, Y. Physicochemical drug properties associated with in vivo toxicological outcomes Bioorg. Med. Chem. Lett. 2008, 18, 4872-4875
145. Gleeson, M. P. Generation of a set of simple, interpretable ADMET rules of thumb J. Med. Chem. 2008, 51, 817-834 (Pubitemid 351304691)
146. Gleeson, P.; Bravi, G.; Modi, S.; Lowe, D. ADMET rules of thumb II: a comparison of the effects of common substituents on a range of ADMET parameters Bioorg. Med. Chem. 2009, 17, 5906-5919
147. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-890 (Pubitemid 350042396)
148. Leeson, P. D.; Empfield, J. R. Reducing the risk of drug attrition associated with physicochemical properties Annu. Rep. Med. Chem. 2010, 45, 393-407
149. Price, D. A.; Blagg, J.; Jones, L.; Greene, N.; Wager, T. Physicochemical drug properties associated with in vivo toxicological outcomes: a review Expert Opin. Drug Metab. Toxicol. 2009, 5, 921-931
150. Waring, M. J. Lipophilicity in drug discovery Expert Opin Drug Discovery 2010, 5, 235-248
151. The Nobel Prize in Chemistry 2010-Richard F. Heck, Ei-ichi Negishi, Akira Suzuki, "For Palladium-Catalyzed Cross Couplings in Organic Synthesis". http://nobelprize.org/nobel-prizes/chemistry/laureates/2010/ (accessed Feb 7, 2011).
152. Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, J. L., Jr.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Key green chemistry research areas, a perspective from pharmaceutical manufacturers Green Chem. 2007, 9, 411-420
153. Alcazar, J.; Oehrlich, D. Recent applications of microwave irradiation to medicinal chemistry Future Med. Chem. 2010, 2, 169-176
154. Kappe, O. C.; Dallinger, D. The impact of microwave synthesis on drug discovery Nat. Rev. Drug Discovery 2006, 5, 51-63
155. Mavandadi, F.; Pilotti, A. The impact of microwave-assisted organic synthesis in drug discovery Drug Discovery Today 2006, 11, 165-174 (Pubitemid 43375968)
156. Santagada, V.; Frecentese, F.; Perissuttu, E.; Fiorino, F.; Severino, B.; Caliendo, G. Microwave assisted synthesis: a new technology in drug discovery Mini-Rev. Med. Chem. 2009, 9, 340-358
157. Ahmed-Omer, B.; Brandt, J. C.; Wirth, T. Advanced organic synthesis using microreactor technology Org. Biomol. Chem. 2007, 5, 733-740
158. Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Greener approaches to organic synthesis using microreactor technology Chem. Rev. 2007, 107, 2300-2318 (Pubitemid 47029095)
159. Jones, R. V.; Csajabi, C.; Szekelyhidi, Z.; Kovacs, I.; Borcsek, B.; Urge, L.; Darvas, F. Flow reactos for drug discovery flow for reaction optimization, library synthesis and scale up Chim. Oggi 2008, 26, 10-12
160. Wiles, C.; Watts, P. Improving chemical synthesis using flow reactors Expert Opin Drug Discovery 2007, 2, 1487-1503 (Pubitemid 350186601)
161. Wiles, C.; Watts, P. Enhanced chemical synthesis in flow reactors Chim. Oggi 2009, 27, 34-36
162. Borshell, N.; Papp, T.; Congreve, M. Deal watch: valuation benefits of structure-enabled drug discovery Nat. Rev. Drug Discovery 2011, 10, 166
163. Czerepak, E. A.; Ryser, S. Drug approvals and failures: implications for alliances Nat. Rev. Drug Discovery 2008, 7, 197-198 (Pubitemid 351321230)
164. Kola, I.; Landis, J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discovery 2004, 3, 711-715 (Pubitemid 39173511)