The impact of aromatic ring count on compound developability – are too many aromatic rings a liability in drug design?

Drug Discovery Today - Tập 14 Số 21-22 - Trang 1011-1020 - 2009
Timothy J. Ritchie1, Simon J. F. Macdonald1
1Respiratory CEDD, GlaxoSmithKline Research Medicines Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK

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Tài liệu tham khảo

Lipinski, 2001, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Deliv. Rev., 46, 3, 10.1016/S0169-409X(00)00129-0

Leeson, 2007, The influence of drug-like concepts on decision-making in medicinal chemistry, Nat. Rev. Drug Discov., 6, 881, 10.1038/nrd2445

Muresan, 2008, Properties guiding drug- and lead-likeness, 10.1002/9783527621286.ch17

Spotfire DXP 2.0 or DecisionSite 8.2.1

Lipinski, 2000, Drug-like properties and the causes of poor solubility and poor permeability, J. Pharmacol. Toxicol. Methods, 44, 235, 10.1016/S1056-8719(00)00107-6

Hann, 2001, Molecular complexity and its impact on the probability of finding leads for drug discovery, J. Chem. Inf. Comput. Sci., 41, 856, 10.1021/ci000403i

Wenlock, 2003, A comparison of physicochemical property profiles of development and marketed oral drugs, J. Med. Chem., 46, 1250, 10.1021/jm021053p

Palm, 1997, Polar molecular surface properties predict the intestinal absorption of drugs in humans, Pharm. Res., 14, 568, 10.1023/A:1012188625088

Veber, 2002, Molecular properties that influence the oral bioavailability of drug candidates, J. Med. Chem., 45, 2615, 10.1021/jm020017n

Hughes, 2008, Physiochemical drug properties associated with in vivo toxicological outcomes, Bioorg. Med. Chem. Lett., 18, 4872, 10.1016/j.bmcl.2008.07.071

Ran, 2001, Prediction of drug solubility by the general solubility equation (GSE), J. Chem. Inf. Comput. Sci., 41, 354, 10.1021/ci000338c

Lamanna, 2008, Straightforward recursive partitioning model for discarding insoluble compounds in the drug discovery process, J. Med. Chem., 51, 2891, 10.1021/jm701407x

Valko, 2003, Fast gradient HPLC method to determine compounds binding to human serum albumin. Relationships with octanol-water and immobilized artificial membrane lipophilicity, J. Pharm. Sci., 92, 2236, 10.1002/jps.10494

Sudlow, 1975, Characterization of two specific drug binding sites on human serum albumin, Mol. Pharmacol., 11, 824

Trainor, 2007, The importance of plasma protein binding in drug discovery, EODC, 2, 51

Lewis, 2002, Substrate SAR in human p450s, Drug Discov. Today, 7, 918, 10.1016/S1359-6446(02)02412-1

Blagg, 2006, Structure activity relationships for in vitro and in vivo toxicity, Annu. Rep. Med. Chem., 41, 353, 10.1016/S0065-7743(06)41024-1

Hop, 2006, Importance of early assessment of bioactivation in drug discovery, Annu. Rep. Med. Chem., 41, 369, 10.1016/S0065-7743(06)41025-3

Jamieson, 2006, Medicinal chemistry of hERG optimizations: highlights and hang-ups, J. Med. Chem., 49, 5029, 10.1021/jm060379l

Wood, 2005, The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS, Prog. Med. Chem., 43, 239, 10.1016/S0079-6468(05)43007-6

Santella, 2008, From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis, Bioorg. Med. Chem. Lett., 18, 576, 10.1016/j.bmcl.2007.11.067

Gardner, 2008, From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part II: acyclic replacements for the (3S)-3-benzylpiperidine in a series of potent CCR3 antagonists, Bioorg. Med. Chem. Lett., 18, 586, 10.1016/j.bmcl.2007.11.087

Leeson, 2004, Time-related differences in the physical property profiles of oral drugs, J. Med. Chem., 47, 6338, 10.1021/jm049717d