Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery

Journal of Medicinal Chemistry

Volumn 58, Issue 22, 2015, Pages 9041-9060

  Huchet, Quentin A ^a   Kuhn, Bernd ^b   Wagner, Björn ^b   Kratochwil, Nicole A ^b   Fischer, Holger ^b   Kansy, Manfred ^b   Zimmerli, Daniel ^b   Carreira, Erick M ^a   Müller, Klaus ^b  

^a ETH ZURICH   (Switzerland)

^b F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

2 (1H INDOL 3 YL) N METHOXY N METHYLACETAMIDE; 3 (1H INDOL 3 YL) N METHOXY N METHYLPROPANAMIDE; 3 (2,2 DIFLUOROBUTYL) 1 TOSYL 1H INDOLE; 3 (2,2 DIFLUOROBUTYL) 1H INDOLE; 3 (2,2 DIFLUOROPROPYL) 1 TOSYL 1H INDOLE; 3 (2,2 DIFLUOROPROPYL) 1H INDOLE; 3 (2,3 DIFLUOROPROPYL) 1 TOSYL 1H INDOLE; 3 (2,3 DIFLUOROPROPYL) 1H INDOLE; 3 (3,3 DIFLUOROBUTYL) 1 TOSYL 1H INDOLE; 3 (3,3 DIFLUOROBUTYL) 1H INDOLE; 3 (3,4 DIFLUOROBUTYL) 1 TOSYL 1H INDOLE; 3 (3,4 DIFLUOROBUTYL) 1H INDOLE; 3 (BUT 3 EN 1 YL) 1 TOSYL 1H INDOLE; 3 (BUT 3 EN 1 YL) 1H INDOLE; 3 (OXIRAN 2 YLMETHYL) 1 TOSYL 1H INDOLE; 3 ALLYL 1 TOSYL 1H INDOLE; 3 ALLYL 1H INDOLE; 3 [2 (OXIRAN 2 YL)ETHYL] 1 TOSYL 1H INDOLE; 4 (1 TOSYL 1H INDOL 3 YL)BUT 2 EN 1 OL; 4 (1 TOSYL 1H INDOL 3 YL)BUT 2 YN 1 OL; ERYTHRO 3 (2,3 DIFLUOROBUTYL) 1H INDOLE; ERYTHRO 3 (2,3,4 TRIFLUOROBUTYL) 1H INDOLE; INDOLE DERIVATIVE; METHYL 4 (1 TOSYL 1H INDOL 3 YL)BUT 2 YNOATE; N METHOXY N METHYL 2 (1 TOSYL 1H INDOL 3 YL)ACETAMIDE; N METHOXY N METHYL 3 (1 TOSYL 1H INDOL 3 YL)PROPANAMIDE; SYN 1 (OXIRAN 2 YL) 2 (1 TOSYL 1H INDOL 3 YL)ETHANOL; THREO 3 (2,3 DIFLUOROBUTYL) 1H INDOLE; THREO 3 (2,3,4 TRIFLUOROBUTYL) 1H INDOLE; UNCLASSIFIED DRUG; UNINDEXED DRUG; FLUORINE DERIVATIVE; LIPID;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; DENSITY FUNCTIONAL THEORY; DIPOLE; DRUG SOLUBILITY; DRUG STABILITY; DRUG SYNTHESIS; FLUORINATION; HUMAN; HUMAN CELL; HUMAN TISSUE; LIPOPHILICITY; METABOLIC STABILITY; NONHUMAN; PHYSICAL CHEMISTRY; RAT; SOLVATION; ANIMAL; BIOTRANSFORMATION; CHEMISTRY; DRUG DESIGN; DRUG DEVELOPMENT; HALOGENATION; IN VITRO STUDY; LIVER MICROSOME; METABOLISM; PROCEDURES; PROTEIN TERTIARY STRUCTURE; SOLUBILITY; STRUCTURE ACTIVITY RELATION; SYNTHESIS; THERMODYNAMICS;

ANIMALS; BIOTRANSFORMATION; CHEMISTRY, PHYSICAL; DRUG DESIGN; DRUG DISCOVERY; FLUORINE COMPOUNDS; HALOGENATION; HUMANS; IN VITRO TECHNIQUES; LIPIDS; MICROSOMES, LIVER; PROTEIN STRUCTURE, TERTIARY; RATS; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; THERMODYNAMICS;

EID: 84948693313     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01455     Document Type: Article

References (49)

1. Kola, I.; Landis, J. Can the Pharmaceutical Industry Reduce Attrition Rates? Nat. Rev. Drug Discovery 2004, 3, 711-715 10.1038/nrd1470
2. Kerns, E. H.; Di, L. Profiling Drug-like Properties in Discovery Research Drug Discovery Today 2003, 8, 316-323 10.1016/S1359-6446(03)02649-7
3. Kerns, E. H.; Di, L. Drug-Like Properties: Concepts, Structure Design and Methods; Academic Press: San Diego, CA, 2008.
4. Lipinski, C. A. Drug-like Properties and the Causes of Poor Solubility and Poor Permeability J. Pharmacol. Toxicol. Methods 2000, 44, 235-249 10.1016/S1056-8719(00)00107-6
5. Bleicher, K. H.; Böhm, H.-J.; Müller, K.; Alanine, A. I. Hit and Lead Generation: Beyond High-throughput Screening Nat. Rev. Drug Discovery 2003, 2, 369-378 10.1038/nrd1086
6. Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities ChemMedChem 2007, 2, 1100-1115 10.1002/cmdc.200700059
7. Lipophilicity in Drug Action and Toxicology; Pliška, V.; Testa, B.; van de Waterbeemd, P.-D. H., Eds.; Wiley: Weinheim, Germany, 2008; Vol. 4, pp 7-386.
8. Van de Waterbeemd, H.; Smith, D. A.; Beaumont, K.; Walker, D. K. Property-based Design: Optimization of Drug Absorption and Pharmacokinetics J. Med. Chem. 2001, 44, 1313-1333 10.1021/jm000407e
9. Grunewald, G. L.; Seim, M. R.; Lu, J.; Makboul, M.; Criscione, K. R. Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination J. Med. Chem. 2006, 49, 2939-2952 10.1021/jm051262k
10. Smart, B. E. Fluorine Substituent Effects (on Bioactivity) J. Fluorine Chem. 2001, 109, 3-11 10.1016/S0022-1139(01)00375-X
11. Swallow, S. Fluorine in Medicinal Chemistry. In Progress in Medicinal Chemistry, 1 st ed.; Lawton, G.; Witty, D., Eds.; Elsevier: Amsterdam, 2015; pp 65-133.
12. Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. Fluorine in Medicinal Chemistry ChemBioChem 2004, 5, 637-643 10.1002/cbic.200301023
13. Müller, K.; Faeh, Ch.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition Science 2007, 317, 1881-1886 10.1126/science.1131943
14. Huchet, Q. A.; Kuhn, B.; Wagner, B.; Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. On the Polarity of Partially Fluorinated Methyl Groups J. Fluorine Chem. 2013, 152, 119-128 Modeling discussed in this publication suggested that the parent 3-butyl indole would be outside the range of log P that would be necessary for proper comparison in our assay of log P described in this study 10.1016/j.jfluchem.2013.02.023
15. Müller, K. Simple Vector Considerations to Assess the Polarity of Partially Fluorinated Alkyl and Alkoxy Groups Chimia 2014, 68, 356-362 10.2533/chimia.2014.356
16. Van de Waterbeemd, H.; Testa, B. The Parameterization of Lipophilicity and other Structural Properties in Drug Design Adv. Drug Res. 1987, 16, 85-225
17. Craig, N. C.; Chen, A.; Suh, K. H.; Klee, S.; Mellau, G. C.; Winnewisser, B. P.; Winnewisser, M. Contribution to the Study of the Gauche Effect. The Complete Structure of the Anti Rotamer of 1,2-Difluoroethane J. Am. Chem. Soc. 1997, 119, 4789-4790 10.1021/ja963819e
18. 2) on the Conformation and Properties of Selected Organic Compounds Pure Appl. Chem. 2012, 84, 1587-1595 10.1351/PAC-CON-11-09-26
19. Hunter, L.; Slawin, A. M. Z.; Kirsch, P.; O'Hagan, D. Synthesis and Conformation of Multi-Vicinal Fluoroalkane Diastereoisomers Angew. Chem., Int. Ed. 2007, 46, 7887-7890 10.1002/anie.200701988
20. Landolt-Börnstein Indexes of Organic Compounds, New Series, II/7, Springer-Verlag: Heidelberg, 1976.
21. Cambridge Structural Database, CSD, version 5.36; Cambridge Crystallographic Data Centre: Cambridge, UK, 2015.
22. Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. Pd-Catalyzed C3-Selective Allylation of Indoles with Allyl Alcohols Promoted by Triethylborane J. Am. Chem. Soc. 2005, 127, 4592-4593 10.1021/ja0501161
23. Colombo, F.; Cravotto, G.; Palmisano, G.; Penoni, A.; Sisti, M. Three-Component Indium-Mediated Domino Allylation of 1H-Indole-3-carbaldehyde with Electron-Rich (Hetero)arenes: Highly Efficient Access to Variously Functionalized Indolylbutenes Eur. J. Org. Chem. 2008, 2008, 2801-2807 10.1002/ejoc.200701160
24. Wang, K.; Liu, Z. Synthesis of Arcyriarubin A and Arcyriaflavin A via Cross-Coupling of Indolylboronic Acid with Dibromomaleimides Synth. Commun. 2009, 40, 144-150 10.1080/00397910902962878
25. Koizumi, Y.; Kobayashi, H.; Wakimoto, T.; Furuta, T.; Fukuyama, T.; Kan, T. Total Synthesis of (-)-Serotobenine J. Am. Chem. Soc. 2008, 130, 16854-16855 10.1021/ja807676v
26. Klar, U.; Neef, G.; Vorbrüggen, H. Perfluorobutanesulfonyl Fluoride-1,8-Diazabicyclo[5.4.0]undec-7-ene as a Useful System in Diol-Epoxide Transformation Tetrahedron Lett. 1996, 37, 7497-7498 10.1016/0040-4039(96)01710-8
27. Voight, E. A.; Yin, H.; Downing, S. V.; Calad, S. A.; Matsuhashi, H.; Giordano, I.; Hennessy, A. J.; Goodman, R. M.; Wood, J. L. Target-Directed Synthesis of Antibacterial Drug Candidate GSK966587 Org. Lett. 2010, 12, 3422-3425 10.1021/ol101235f
28. Hamatani, T.; Matsubara, S.; Matsuda, H.; Schlosser, M. A stereocontrolled Access to Vicinal Difluoroalkanes Tetrahedron 1988, 44, 2875-2881 10.1016/S0040-4020(88)90023-3
29. Yin, J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.; Huffman, M. A. Direct and Convenient Conversion of Alcohols to Fluorides Org. Lett. 2004, 6, 1465-1468 10.1021/ol049672a
30. MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Rapid Synthesis of the N-Methylwelwitindolinone Skeleton Org. Lett. 2005, 7, 3421-3424 10.1021/ol051043t
31. Duval, E.; Cuny, G. D. Synthesis of Substituted Carbazoles and β-Carbolines by Cyclization of Diketoindole Derivatives Tetrahedron Lett. 2004, 45, 5411-5413 10.1016/j.tetlet.2004.05.053
32. Dow, R. L.; Carpino, P. A.; Hadcock, J. R.; Black, S. C.; Iredale, P. A.; DaSilva-Jardine, P.; Schneider, S. R.; Paight, E. S.; Griffith, D. A.; Scott, D. O.; O'Connor, R. E.; Nduaka, C. I. Discovery of 2-(2-Chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (PF-514273), a Novel, Bicyclic Lactam-Based Cannabinoid-1 Receptor Antagonist for the Treatment of Obesity J. Med. Chem. 2009, 52, 2652-2655 10.1021/jm900255t
33. Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. Discovery of 4-tert-Butyl-2,6-dimethylphenylsulfur Trifluoride as a Deoxofluorinating Agent with High Thermal Stability as Well as Unusual Resistance to Aqueous Hydrolysis, and Its Diverse Fluorination Capabilities Including Deoxofluoro-Arylsulfinylation with High Stereoselectivity J. Am. Chem. Soc. 2010, 132, 18199-18205 10.1021/ja106343h
34. Le Borgne, M.; Na, Y. M.; Pagniez, F.; Le Baut, G.; Le Pape, P.; Abdala, H. Antifungal and/or Antiparasitic Pharmaceutical Composition and Novel Indole Derivatives as Active Principle of such a Composition. PCT Int. Appl. WO 2002 024685 A1 2002.
35. Davies, K. A.; Abel, R. C.; Wulff, J. E. Operationally Simple Copper-Promoted Coupling of Terminal Alkynes with Benzyl Halides J. Org. Chem. 2009, 74, 3997-4000 10.1021/jo900444x
36. Barker, S. A.; Foster, A. B.; Lamb, D. C.; Jackman, L. M. Components of Royal Jelly Tetrahedron 1962, 18, 177-181 10.1016/0040-4020(62)80037-4
37. Keck, G. E.; Dougherty, S. M.; Savin, K. A. Intramolecular Allylstannane-Aldehyde Cyclizations: Stereochemical Results with Flexible Tethers for Reactions Forming Vinylcyclohexanols J. Am. Chem. Soc. 1995, 117, 6210-6223 10.1021/ja00128a007
38. 4 J. Org. Chem. 2006, 71, 6420-6426 10.1021/jo0606756
39. Goswami, K.; Paul, S.; Bugde, S. T.; Sinha, S. Synthesis of Optically Active Homotryptophan and its Oxygen and Sulfur Analogues Tetrahedron 2012, 68, 280-286 10.1016/j.tet.2011.10.055
40. Fox, S. J.; Gourdain, S.; Coulthurst, A.; Fox, C.; Kuprov, I.; Essex, J. W.; Skylaris, C.-K.; Linclau, B. A Computational Study of Vicinal Fluorination in 2,3-Difluorobutane: Implications for Conformational Control in Alkane Chains Chem.-Eur. J. 2015, 21, 1682-1691 10.1002/chem.201405317
41. Mannhold, R.; Rekker, R. F. The Hydrophobic Fragmental Constant Approach for Calculating log P in Octanol/Water and Aliphatic Hydrocarbon/Water Systems Perspect. Drug Discovery Des. 2000, 18, 1-18 10.1023/A:1008782809845
42. Lipinski, C.; Lombardo, F.; Dominy, B.; Feeney, P. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings Adv. Drug Delivery Rev. 1997, 23, 3-25 10.1016/S0169-409X(96)00423-1
43. Van de Waterbeemd, H. The Fundamental Variables of the Biopharmaceutics Classification System (BCS): a Commentary Eur. J. Pharm. Sci. 1998, 7, 1-3 10.1016/S0928-0987(98)00051-7
44. French, A. N.; Napolitano, E.; VanBrocklin, H. F.; Brodack, J. W.; Hanson, R. N.; Welch, M. J.; Katzenellenbogen, J. A. The β-Heteroatom Effect in Metabolic Defluorination the Interaction of Resonance and Inductive Effects may be a Fundamental Determinant in the Metabolic Liability of Fluorine-Substituted Compounds J. Labelled Compd. Radiopharm 1991, 30, 431-433
45. French, A. N.; Napolitano, E.; VanBrocklin, H. F.; Hanson, R. N.; Welch, M. J.; Katzenellenbogen, J. A. Synthesis, Radiolabeling and Tissue Distribution of 11-β-fluoroalkyl-substituted and 11-β-fluoroalkoxy-substituted Estrogens-Target Tissue Uptake Selectivity and Defluorination of a Homologous Series of Fluorine-18-labeled Estrogens Nucl. Med. Biol. 1993, 20, 31-47 10.1016/0969-8051(93)90134-G
46. Gerber, P.; Müller, K. MAB, A Generally Applicable Molecular-Force Field For Structure Modeling in Medicinal Chemistry J. Comput.-Aided Mol. Des. 1995, 9, 251-268 10.1007/BF00124456
47. Jaguar, version 7.7; Schrödinger LLC: New York, 2010.
48. Tannor, D. J.; Marten, B.; Murphy, R.; Friesner, R. A.; Sitkoff, D.; Nicholls, A.; Ringnalda, M.; Goddard, W. A., III; Honig, B. Accurate First Principles Calculation of Molecular Charge Distributions and Solvation Energies from Ab Initio Quantum Mechanics and Continuum Dielectric Theory J. Am. Chem. Soc. 1994, 116, 11875-11882 10.1021/ja00105a030
49. Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. A Practical Approach to the Synthesis of 2,4-Disubstituted Oxazoles from Amino Acids Org. Lett. 2002, 4, 2665-2668 10.1021/ol020092s