Simon J F Macdonald

Publications (25)105.18 Total impact

• Article: The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types.

  Timothy J Ritchie, Simon J F Macdonald, Robert J Young, Stephen D Pickett
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  ABSTRACT: The impact of carboaromatic, heteroaromatic, carboaliphatic and heteroaliphatic ring counts and fused aromatic ring count on several developability measures (solubility, lipophilicity, protein binding, P450 inhibition and hERG binding) is the topic for this review article. Recent results indicate that increasing ring counts have detrimental effects on developability in the order carboaromatics≫heteroaromatics>carboaliphatics>heteroaliphatics, with heteroaliphatics exerting a beneficial effect in many cases. Increasing aromatic ring count exerts effects on several developability parameters that are lipophilicity- and size-independent, and fused aromatic systems have a beneficial effect relative to their nonfused counterparts. Increasing aromatic ring count has a detrimental effect on human bioavailability parameters, and heteroaromatic ring count (but not other ring counts) has increased over time in marketed oral drugs.
  Drug discovery today 02/2011; 16(3-4):164-71. · 6.63 Impact Factor
• Article: Discovery of a potent series of non-steroidal non α-trifluoromethyl carbinol glucocorticoid receptor agonists with reduced lipophilicity.

  Hawa Diallo, Davina C Angell, Heather A Barnett, Keith Biggadike, Diane M Coe, Tony W J Cooper, Andy Craven, James R Gray, David House, Torquil I Jack, Steve P Keeling, Simon J F Macdonald, Iain M McLay, Samuel Oliver, Simon J Taylor, Iain J Uings, Natalie Wellaway
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  ABSTRACT: A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology.
  Bioorganic & medicinal chemistry letters 02/2011; 21(4):1126-33. · 2.65 Impact Factor
• Article: Factors determining the selection of organic reactions by medicinal chemists and the use of these reactions in arrays (small focused libraries).

  Tony W J Cooper, Ian B Campbell, Simon J F Macdonald
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  ABSTRACT: Synthetic organic reactions are a fundamental enabler of small-molecule drug discovery, and the vast majority of medicinal chemists are initially trained--either at universities or within industry--as synthetic organic chemists. The sheer breadth of synthetic methodology available to the medicinal chemist represents an almost endless source of innovation. But what reactions do medicinal chemists use in drug discovery? And what criteria do they use in selecting synthetic methodology? Why are arrays (small focused libraries) so powerful in the lead-optimization process? In this Minireview, we suggest some answers to these questions and also describe how we have tried to expand the number of robust reactions available to the medicinal chemist.
  Angewandte Chemie International Edition 10/2010; 49(44):8082-91. · 13.45 Impact Factor
• Article: Lead optimization using matched molecular pairs: inclusion of contextual information for enhanced prediction of HERG inhibition, solubility, and lipophilicity.

  George Papadatos, Muhammad Alkarouri, Valerie J Gillet, Peter Willett, Visakan Kadirkamanathan, Christopher N Luscombe, Gianpaolo Bravi, Nicola J Richmond, Stephen D Pickett, Jameed Hussain, John M Pritchard, Anthony W J Cooper, Simon J F Macdonald
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  ABSTRACT: Previous studies of the analysis of molecular matched pairs (MMPs) have often assumed that the effect of a substructural transformation on a molecular property is independent of the context (i.e., the local structural environment in which that transformation occurs). Experiments with large sets of hERG, solubility, and lipophilicity data demonstrate that the inclusion of contextual information can enhance the predictive power of MMP analyses, with significant trends (both positive and negative) being identified that are not apparent when using conventional, context-independent approaches.
  Journal of Chemical Information and Modeling 10/2010; 50(10):1872-86. · 4.68 Impact Factor
• Article: Faktoren für die Auswahl organischer Reaktionen in der medizinischen Chemie und die Anwendung dieser Reaktionen in Arrays (kleinen fokussierten Bibliotheken)

  Tony W. J. Cooper, Ian B. Campbell, Simon J. F. Macdonald
  Angewandte Chemie 09/2010; 122(44):8258 - 8267.
• Article: Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor.

  Keith Biggadike, Randy K Bledsoe, Diane M Coe, Tony W J Cooper, David House, Marie A Iannone, Simon J F Macdonald, Kevin P Madauss, Iain M McLay, Tracy J Shipley, Simon J Taylor, Thuy B Tran, Iain J Uings, Victoria Weller, Shawn P Williams
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  ABSTRACT: Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14. Data with the pyrrolidinone amide 12 demonstrate the potential for further elaboration within the "meta" channel to deliver compounds with selectivity for the desired transrepressive activity of glucocorticoids. The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators.
  Proceedings of the National Academy of Sciences 10/2009; 106(43):18114-9. · 9.68 Impact Factor
• Article: Highly tractable, sub-nanomolar non-steroidal glucocorticoid receptor agonists.

  Keith Biggadike, Matilde Caivano, Margaret Clackers, Diane M Coe, George W Hardy, Davina Humphreys, Haydn T Jones, David House, Annette Miles-Williams, Philip A Skone, Iain Uings, Vicki Weller, Iain M McLay, Simon J F Macdonald
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  ABSTRACT: Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFkappaB agonist activity was optimised in an iterative process from pIC(50) 7.5 (for 7), to pIC(50) 10.1 (for 38E1). An explanation for the SAR observed based is presented along with a proposed docking of 38E1 into the active site of the glucocorticoid receptor.
  Bioorganic & medicinal chemistry letters 09/2009; 19(16):4846-50. · 2.65 Impact Factor
• Source

  Available from: ufrj.br

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

  Timothy J Ritchie, Simon J F Macdonald
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  ABSTRACT: The impact of aromatic ring count (the number of aromatic and heteroaromatic rings) in molecules has been analyzed against various developability parameters - aqueous solubility, lipophilicity, serum albumin binding, CyP450 inhibition and hERG inhibition. On the basis of this analysis, it was concluded that the fewer aromatic rings contained in an oral drug candidate, the more developable that candidate is probably to be; in addition, more than three aromatic rings in a molecule correlates with poorer compound developability and, thus, an increased risk of attrition in development. Data are also presented that demonstrate that even within a defined lipophilicity range, increased aromatic ring count leads to decreased aqueous solubility.
  Drug discovery today 09/2009; 14(21-22):1011-20. · 6.63 Impact Factor
• Article: Analysis of the calculated physicochemical properties of respiratory drugs: can we design for inhaled drugs yet?

  Timothy J Ritchie, Christopher N Luscombe, Simon J F Macdonald
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  ABSTRACT: From an analysis of calculated physicochemical properties for 81 currently marketed respiratory drugs, compounds administered via the inhaled/intranasal routes have a higher polar surface area, a higher molecular weight, and a trend toward lower lipophilicity, when compared with their orally administered counterparts. Ranges of physicochemical space are described for the 29 drugs administered by the inhaled or intranasal routes.
  Journal of Chemical Information and Modeling 04/2009; 49(4):1025-32. · 4.68 Impact Factor
• Article: Analysis of neighborhood behavior in lead optimization and array design.

  George Papadatos, Anthony W J Cooper, Visakan Kadirkamanathan, Simon J F Macdonald, Iain M McLay, Stephen D Pickett, John M Pritchard, Peter Willett, Valerie J Gillet
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  ABSTRACT: Neighborhood behavior describes the extent to which small structural changes defined by a molecular descriptor are likely to lead to small property changes. This study evaluates two methods for the quantification of neighborhood behavior: the optimal diagonal method of Patterson et al. and the optimality criterion method of Horvath and Jeandenans. The methods are evaluated using twelve different types of fingerprint (both 2D and 3D) with screening data derived from several lead optimization projects at GlaxoSmithKline. The principal focus of the work is the design of chemical arrays during lead optimization, and the study hence considers not only biological activity but also important drug properties such as metabolic stability, permeability, and lipophilicity. Evidence is provided to suggest that the optimality criterion method may provide a better quantitative description of neighborhood behavior than the optimal diagonal method.
  Journal of Chemical Information and Modeling 03/2009; 49(2):195-208. · 4.68 Impact Factor
• Article: Aryl aminopyrazole benzamides as oral non-steroidal selective glucocorticoid receptor agonists.

  Heather A Barnett, Diane M Coe, Tony W J Cooper, Torquil I Jack, Haydn T Jones, Simon J F Macdonald, Iain M McLay, Natalie Rayner, Rosemary Z Sasse, Tracy J Shipley, Phil A Skone, Graham I Somers, Simon Taylor, Iain J Uings, James M Woolven, Gordon G Weingarten
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  ABSTRACT: Aryl aminopyrazole amides capped with N-alkylbenzamides 13-16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxyethyl benzamides (e.g., 16e).
  Bioorganic & medicinal chemistry letters 12/2008; 19(1):158-62. · 2.65 Impact Factor
• Article: Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity.

  Keith Biggadike, Mohamed Boudjelal, Margaret Clackers, Diane M Coe, Derek A Demaine, George W Hardy, Davina Humphreys, Graham G A Inglis, Michael J Johnston, Haydn T Jones, David House, Richard Loiseau, Deborah Needham, Philip A Skone, Iain Uings, Gemma Veitch, Gordon G Weingarten, Iain M McLay, Simon J F Macdonald
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  ABSTRACT: The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFkappaB agonism with pIC50 of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFkappaB agonism with pIC50 of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC50 of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.
  Journal of Medicinal Chemistry 01/2008; 50(26):6519-34. · 5.25 Impact Factor
• Article: Non-steroidal glucocorticoid agonists: the discovery of aryl pyrazoles as A-ring mimetics.

  Margaret Clackers, Diane M Coe, Derek A Demaine, George W Hardy, Davina Humphreys, Graham G A Inglis, Michael J Johnston, Haydn T Jones, David House, Richard Loiseau, Doug J Minick, Philip A Skone, Iain Uings, Iain M McLay, Simon J F Macdonald
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  ABSTRACT: Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NFkappaB pIC(50) 8.1 (103%), MMTV pEC(50) 7.02 (36%)). The tetrahydronaphthalene moiety can also be replaced with substituted aryls such as 24E1 and 25E1.
  Bioorganic & Medicinal Chemistry Letters 10/2007; 17(17):4737-45. · 2.55 Impact Factor
• Article: Carbon-carbon bond forming reactions with substrates absorbed non-covalently on a cellulose chromatography paper support.

  Jonathon Hacon, Amanda Morris, Michael J Johnston, Stephen E Shanahan, Mike D Barker, Graham G A Inglis, Simon J F Macdonald
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  ABSTRACT: Reactions and purifications, including carbon-carbon bond forming reactions, can be carried out on a cellulose support on which the substrates are non-covalently absorbed.
  Chemical Communications 03/2007; · 6.17 Impact Factor
• Article: Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series.

  Mike Barker, Margaret Clackers, Royston Copley, Derek A Demaine, Davina Humphreys, Graham G A Inglis, Michael J Johnston, Haydn T Jones, Michael V Haase, David House, [......], Francois Pacquet, Philip A Skone, Stephen E Shanahan, Dan Tape, Victoria M Vinader, Melanie Washington, Iain Uings, Richard Upton, Iain M McLay, Simon J F Macdonald
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  ABSTRACT: The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.
  Journal of Medicinal Chemistry 08/2006; 49(14):4216-31. · 5.25 Impact Factor
• Article: Design and synthesis of new nonsteroidal glucocorticoid modulators through application of an "agreement docking" method.

  Mike Barker, Margaret Clackers, Derek A Demaine, Davina Humphreys, Michael J Johnston, Haydn T Jones, Francois Pacquet, John M Pritchard, Mark Salter, Stephen E Shanahan, Philip A Skone, Victoria M Vinader, Iain Uings, Iain M McLay, Simon J F Macdonald
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  ABSTRACT: Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a is a partial agonist while 9e and 15a are micromolar antagonists in a mouse mammary tumor virus transactivation assay.
  Journal of Medicinal Chemistry 08/2005; 48(14):4507-10. · 5.25 Impact Factor
• Article: Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza.

  Simon J F Macdonald, Rachel Cameron, Derek A Demaine, Rob J Fenton, Graham Foster, David Gower, J Nicole Hamblin, Stephanie Hamilton, Graham J Hart, Alan P Hill, [......], Jennifer McKimm-Breschkin, Gail Mills, Van Nguyen, Ian J Owens, Nigel Parry, Stephen E Shanahan, Donna Smith, Keith G Watson, Wen-Yang Wu, Simon P Tucker
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  ABSTRACT: The synthesis, antiviral and pharmacokinetic properties of zanamivir (ZMV) dimers 8 and 13 are described. The compounds are highly potent neuraminidase (NA) inhibitors which, along with dimer 3, are being investigated as potential second generation inhaled therapies both for the treatment of influenza and for prophylactic use. They show outstanding activity in a 1 week mouse influenza prophylaxis assay, and compared with ZMV, high concentrations of 8 and 13 are found in rat lung tissue after 1 week. Retention of compounds in rat lung tissue correlated both with molecular weight (excluding 3 and 15) and with a capacity factor K' derived from immobilized artificial membrane (IAM) chromatography (including 3 and 15). Pharmacokinetic parameters for 3, 8 and 13 in rats show the compounds have short to moderate plasma half-lives, low clearances and low volumes of distribution. Dimer 3 shows NA inhibitory activity against N1 viruses including the recent highly pathogenic H5N1 A/Chicken/Vietnam/8/2004. In plaque reduction assays, 3, 8 and 13 show good to outstanding potency against a panel of nine flu A and B virus strains. Consistent with its shorter and more rigid linking group, dimer 8 has been successfully crystallized.
  Journal of Medicinal Chemistry 05/2005; 48(8):2964-71. · 5.25 Impact Factor
• Source

  Available from: ncbi.nlm.nih.gov

  Article: Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at a once-weekly dosing regimen.

  Simon J F Macdonald, Keith G Watson, Rachel Cameron, David K Chalmers, Derek A Demaine, Rob J Fenton, David Gower, J Nicole Hamblin, Stephanie Hamilton, Graham J Hart, [......], Darryl B McConnell, Andy M Mason, Van Nguyen, Ian J Owens, Nigel Parry, Phillip A Reece, Stephen E Shanahan, Donna Smith, Wen-Yang Wu, Simon P Tucker
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  ABSTRACT: Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 A, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.
  Antimicrobial Agents and Chemotherapy 01/2005; 48(12):4542-9. · 4.84 Impact Factor
• Article: Highly potent and long-acting trimeric and tetrameric inhibitors of influenza virus neuraminidase.

  Keith G Watson, Rachel Cameron, Rob J Fenton, David Gower, Stephanie Hamilton, Betty Jin, Guy Y Krippner, Angela Luttick, Darryl McConnell, Simon J F MacDonald, Andy M Mason, Van Nguyen, Simon P Tucker, Wen-Yang Wu
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  ABSTRACT: A set of trimeric and tetrameric derivatives 6-11 of the influenza virus neuraminidase inhibitor zanamivir 1 have been synthesized by coupling a common monomeric zanamivir derivative 3 onto various multimeric carboxylic acid core groups. These discrete multimeric compounds are all significantly more antiviral than zanamivir and also show outstanding long-lasting protective activity when tested in mouse influenza infectivity experiments.
  Bioorganic & Medicinal Chemistry Letters 04/2004; 14(6):1589-92. · 2.55 Impact Factor
• Article: The design of novel N-4'-pyridinyl-alpha-methyl proline derivatives as potent catalysts for the kinetic resolution of alcohols.

  Ghislaine Priem, Béatrice Pelotier, Simon J F Macdonald, Mike S Anson, Ian B Campbell
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  ABSTRACT: A novel family of chiral acylation catalysts based on a N-4'-pyridinyl-alpha-methyl proline structure has been studied. A set of 31 compounds has been easily prepared and screened in the kinetic resolution of racemic alcohol 33 resulting in high enantioselectivities in most cases. From results obtained, H-bonding interactions between the catalyst and the substrate would appear essential to afford high enantioselectivity during the catalytic acylation. Additional solvent dependence and anhydride studies have been made to better identify the mechanism. This work has been further extended to the study of a number of structurally different alcohols. Ethanolamine derivatives in particular were found to be highly effective substrates (up to S = 18.8) in the kinetic resolution.
  The Journal of Organic Chemistry 06/2003; 68(10):3844-8. · 4.45 Impact Factor