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Articles

Fraction Lipophilicity Index (FLI). A drug-like metric for orally administered ionizable drugs

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Pages 643-653 | Received 25 Jun 2019, Accepted 05 Aug 2019, Published online: 30 Aug 2019

References

  • P.D. Leeson and B. Springthorpe, The influence of drug-like concepts on decision-making in medicinal chemistry, Nat. Rev. Drug. Discov. 11 (2007), pp. 881–890. doi:10.1038/nrd2445.
  • I. Yusof and M.D. Segall, Considering the impact drug-like properties have on the chance of success, Drug. Discover. Today 18 (2013), pp. 659–666. doi:10.1016/j.drudis.2013.02.008.
  • J.D. Hughes, J. Blagg, D.A. Price, S. Bailey, G.A. Decrescenzo, R.V. Devraj, E. Ellsworth, Y.M. Fobian, M.E. Gibbs, R.W. Gilles, N. Greene, E. Huang, T. Krieger-Burke, J. Loesel, T. Wager, L. Whiteley, and Y. Zhang, Physicochemical drug properties associated with in vivo toxicological outcomes, Bioorg. Med. Chem. Lett. 18 (2008), pp. 4872–4875. doi:10.1016/j.bmcl.2008.07.071.
  • M. Wenlock, R.P. Austin, P. Barton, A.M. Davis, and P.D. Leeson, A comparison of physiochemical property profiles of development and marketed oral drugs, J. Med. Chem. 46 (2003), pp. 1250–1256. doi:10.1021/jm021053p.
  • G.R. Bickerton, G.V. Paolini, J. Besnard, S. Muresan, and A.L. Hopkins, Quantifying the chemical beauty of drugs, Nat. Chem. 4 (2012), pp. 90–98. doi:10.1038/nchem.1243.
  • C. Hansch, J.P. Bjorkroth, and A. Leo, Hydrophobicity and central nervous system agents: On the principle of minimal hydrophobicity in drug design, J. Pharm. Sci. 76 (1987), pp. 66–687. doi:10.1002/jps.2600760902.
  • C.A. Lipinski, F. Lombardo, B.W. Dominy, and P.J. Feeney, In vitro models for selection of development candidates. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug. Deliv. Rev. 23 (1997), pp. 3–25. doi:10.1016/S0169-409X(96)00423-1.
  • M. Congreve, R. Carr, C. Murray, and H. Jhoti, A “rule of three” for fragment-based lead discovery? Drug. Discov. Today. 8 (2003), pp. 876–877. doi:10.1016/S1359-6446(03)02831-9.
  • D.F. Veber, S.R. Johnson, H.-Y. Cheng, B.R. Smith, K.W. Ward, and K.D. Kopple, Molecular properties that influence the oral bioavailability of drug candidates, J. Med. Chem. 45 (2002), pp. 2615–2623. doi:10.1021/jm020017n.
  • T.I. Oprea, Current trends in lead discovery: Are we looking for the appropriate properties? J. Comput. Aided. Mol. Des. 16 (2002), pp. 325–334.
  • T.J. Ritchie and S.J.F. Macdonald, How drug-like are ‘ugly’ drugs: Do drug-likeness metrics predict ADME behaviour in humans? Drug. Discover. Today 19 (2014), pp. 489–495. doi:10.1016/j.drudis.2014.01.007.
  • M.M. Hann, Molecular obesity, potency and other addictions in drug discovery, Med. Chem. Comm. 2 (2011), pp. 349–355. doi:10.1039/c1md00017a.
  • A.L. Hopkins, C.R. Groom, and A. Alex, Ligand efficiency: A useful metric for lead selection, Drug. Discover. Today 9 (2004), pp. 430–431. doi:10.1016/S1359-6446(04)03069-7.
  • A.L. Hopkins, G.M. Keserü, P.D. Leeson, D.C. Rees, and C.M. Reynolds, The role of ligand efficiency metrics in drug discovery, Nat. Rev. Drug. Discover. 13 (2014), pp. 105–121. doi:10.1038/nrd4163.
  • G.M. Keserű and G.M. Makara, The influence of lead discovery strategies on the properties of drug candidates, Nat. Rev. Drug. Discov. 8 (2009), pp. 203–212. doi:10.1038/nrd2796.
  • Y.C. Martin, A bioavailability score, J. Med. Chem. 48 (2005), pp. 3164–3170. doi:10.1021/jm0492002.
  • G. Vistoli, A. Predretti, and B. Testa, Assessing drug-likeness–what are we missing? Drug. Discov. Today 13 (2008), pp. 285–294. doi:10.1016/j.drudis.2007.11.007.
  • J.E.A. Comer High-throughput Measurement of log D and pKa, in Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability, H. van de Waterbeemd, H. Lennernas, and P. Artursson, eds., WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2003, pp. 2.1, 23.
  • M.J. Waring, Defining optimum lipophilicity and molecular weight ranges for drug candidates – Molecular weight dependent lower log D limits based on permeability, Biorg. Med. Chem. Lett. 19 (2009), pp. 2844–2851. doi:10.1016/j.bmcl.2009.03.109.
  • B. Testa, P.A. Carrupt, P. Gaillard, and R.-S. Tsai, Intramolecular interactions encoded in lipophilicity: Their nature and significance, in Lipophilicity in Drug Action and Toxicology, V. Pliska, B. Testa, and H. van de Waterbeemd, eds., VCH, Weinheim, 1995, pp. 49–71.
  • A. Tsantili-Kakoulidou, M. Chatzopoulou, and V.J. Demopoulos, Fraction lipophilicity index (FLI): A metric for assessing oral drug-likeness of ionizable chemical entities, IJQSPR 4 (2019), pp. 41–66.
  • M.D. Shultz, Two decades under the influence of the rule of five and the changing properties of approved oral drugs, J. Med. Chem. 62 (2019), pp. 1701–1714. doi:10.1021/acs.jmedchem.8b00686.
  • D. Newby, A. Freitas, and T. Ghafourian, Decision trees to characterise the roles of permeability and solubility on the prediction of oral absorption, Eur. J. Med. Chem. 90 (2015), pp. 751–765. doi:10.1016/j.ejmech.2014.12.006.
  • V.E. Thiel-Demby, J.E. Humphreys, L.A. St. John Williams, H.M. Ellens, N. Shah, A.D. Ayrton, and J.W. Polli, Biopharmaceutics classification system: Validation and learnings of an in vitro permeability assay, Mol. Pharmaceut. 6 (2009), pp. 11–18. doi:10.1021/mp800122b.
  • M.P. Gleeson, A. Hersey, D. Montanari, and J. Overington, Probing the links between in vitro potency, ADMET and physicochemical parameters, Nat. Rev. Drug. Discov. 3 (2011), pp. 197–208. doi:10.1038/nrd3367.
  • H.A. Zhong, V. Mashinson, T.A. Woolman, and M. Zha, Understanding the molecular properties and metabolism of top prescribed drugs, Curr. Top. Med. Chem. 13 (2013), pp. 1290–1307.

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