Andrew G Leach

Summary

Affiliation: AstraZeneca R and D

Publications

  1. ncbi request reprint Unexpected syn hydride migration in the non-aldol aldol reaction
    Michael E Jung
    Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095 1569, USA
    Org Lett 5:3375-8. 2003
  2. ncbi request reprint Binding affinities of host-guest, protein-ligand, and protein-transition-state complexes
    K N Houk
    Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095 1569, USA
    Angew Chem Int Ed Engl 42:4872-97. 2003
  3. doi request reprint Reaction energies computed with density functional theory correspond with a whole organism effect; modelling the Ames test for mutagenicity
    Andrew G Leach
    AstraZeneca Pharmaceuticals, 50S27 Mereside, Alderley Park, Macclesfield, UKSK10 4TG
    Chem Commun (Camb) . 2009
  4. ncbi request reprint Matched molecular pairs as a guide in the optimization of pharmaceutical properties; a study of aqueous solubility, plasma protein binding and oral exposure
    Andrew G Leach
    AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield SK10 4TG, UK
    J Med Chem 49:6672-82. 2006
  5. doi request reprint Inhibitors of the tyrosine kinase EphB4. Part 2: structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines
    Catherine Bardelle
    AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
    Bioorg Med Chem Lett 18:5717-21. 2008
  6. doi request reprint Use of small-molecule crystal structures to address solubility in a novel series of G protein coupled receptor 119 agonists: optimization of a lead and in vivo evaluation
    James S Scott
    Cardiovascular and Gastrointestinal Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
    J Med Chem 55:5361-79. 2012
  7. doi request reprint Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonists
    James S Scott
    Innovative Medicines Unit, AstraZeneca Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U K
    J Med Chem 57:8984-98. 2014
  8. doi request reprint Protein-ligand crystal structures can guide the design of selective inhibitors of the FGFR tyrosine kinase
    Richard A Norman
    AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, SK10 4TG, U K
    J Med Chem 55:5003-12. 2012
  9. doi request reprint Inhibitors of the tyrosine kinase EphB4. Part 1: Structure-based design and optimization of a series of 2,4-bis-anilinopyrimidines
    Catherine Bardelle
    AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
    Bioorg Med Chem Lett 18:2776-80. 2008
  10. doi request reprint Quantitatively interpreted enhanced inhibition of cytochrome P450s by heteroaromatic rings containing nitrogen
    Andrew G Leach
    AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom
    J Chem Inf Model 51:1048-63. 2011

Collaborators

Detail Information

Publications22

  1. ncbi request reprint Unexpected syn hydride migration in the non-aldol aldol reaction
    Michael E Jung
    Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095 1569, USA
    Org Lett 5:3375-8. 2003
    ..Calculations suggest that this unusual reaction proceeds via the carbocation, which cannot easily rotate due to steric hindrance...
  2. ncbi request reprint Binding affinities of host-guest, protein-ligand, and protein-transition-state complexes
    K N Houk
    Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095 1569, USA
    Angew Chem Int Ed Engl 42:4872-97. 2003
    ..Enzymes transcend this effect and achieve transition-state binding much greater than is expected from the surface areas...
  3. doi request reprint Reaction energies computed with density functional theory correspond with a whole organism effect; modelling the Ames test for mutagenicity
    Andrew G Leach
    AstraZeneca Pharmaceuticals, 50S27 Mereside, Alderley Park, Macclesfield, UKSK10 4TG
    Chem Commun (Camb) . 2009
    ..A series of reactions of anilines and their metabolites have been treated with density functional theory to investigate if any of the computed energy changes correlate with mutagenicity...
  4. ncbi request reprint Matched molecular pairs as a guide in the optimization of pharmaceutical properties; a study of aqueous solubility, plasma protein binding and oral exposure
    Andrew G Leach
    AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield SK10 4TG, UK
    J Med Chem 49:6672-82. 2006
    ..In this paper, we focus upon the effects on aqueous solubility, plasma protein binding and oral exposure of adding substituents to aromatic rings and methylating heteroatoms...
  5. doi request reprint Inhibitors of the tyrosine kinase EphB4. Part 2: structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines
    Catherine Bardelle
    AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
    Bioorg Med Chem Lett 18:5717-21. 2008
    ..The observed range of cellular activities has been rationalised on the basis of physicochemical and structural characteristics...
  6. doi request reprint Use of small-molecule crystal structures to address solubility in a novel series of G protein coupled receptor 119 agonists: optimization of a lead and in vivo evaluation
    James S Scott
    Cardiovascular and Gastrointestinal Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
    J Med Chem 55:5361-79. 2012
    ..The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism...
  7. doi request reprint Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonists
    James S Scott
    Innovative Medicines Unit, AstraZeneca Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U K
    J Med Chem 57:8984-98. 2014
    ..Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119. ..
  8. doi request reprint Protein-ligand crystal structures can guide the design of selective inhibitors of the FGFR tyrosine kinase
    Richard A Norman
    AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, SK10 4TG, U K
    J Med Chem 55:5003-12. 2012
    ..Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form...
  9. doi request reprint Inhibitors of the tyrosine kinase EphB4. Part 1: Structure-based design and optimization of a series of 2,4-bis-anilinopyrimidines
    Catherine Bardelle
    AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
    Bioorg Med Chem Lett 18:2776-80. 2008
    ..A series of bis-anilinopyrimidines have been identified as potent inhibitors of the tyrosine kinase EphB4. Structural information from two alternative series identified from screening efforts was combined to identify the initial leads...
  10. doi request reprint Quantitatively interpreted enhanced inhibition of cytochrome P450s by heteroaromatic rings containing nitrogen
    Andrew G Leach
    AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom
    J Chem Inf Model 51:1048-63. 2011
    ..The computational protocol devised was used to make predictions about a set of as yet unknown heteroaromatic compounds suggested by Pitt et al. ..
  11. doi request reprint Rationally designing safer anilines: the challenging case of 4-aminobiphenyls
    Alan M Birch
    AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK
    J Med Chem 55:3923-33. 2012
    ..The calculations provided SAR-like information that was able guide the design of further examples of 4-aminobiphenyls that are not active in the Ames test...
  12. doi request reprint The discovery of benzanilides as c-Met receptor tyrosine kinase inhibitors by a directed screening approach
    Joanne V Allen
    AstraZeneca R and D, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
    Bioorg Med Chem Lett 21:5224-9. 2011
    ..Structure-activity relationships and molecular modeling have suggested a binding mode for the most potent inhibitor 12...
  13. doi request reprint Free-Wilson and structural approaches to co-optimizing human and rodent isoform potency for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors
    Frederick W Goldberg
    AstraZeneca, Mereside, Alderley Park, Macclesfield, SK10 4TG, United Kingdom
    J Med Chem 55:10652-61. 2012
    ....
  14. doi request reprint Side chain flexibilities in the human ether-a-go-go related gene potassium channel (hERG) together with matched-pair binding studies suggest a new binding mode for channel blockers
    Ulrich Zachariae
    Physical and Computational Chemistry, AstraZeneca, Mereside, Alderley Park, Macclesfield SK11 4TG, UK
    J Med Chem 52:4266-76. 2009
    ..The binding model also suggests a molecular mechanism for the link between high-affinity hERG binding and C-type inactivation...
  15. doi request reprint Experimental testing of quantum mechanical predictions of mutagenicity: aminopyrazoles
    Andrew G Leach
    AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
    Chem Res Toxicol 26:703-9. 2013
    ..The subsequently generated results of the Ames test were in good correspondence with the predictions and confirm this approach as a useful means of predicting likely mutagenic risk...
  16. doi request reprint A system for encoding and searching Markush structures
    David A Cosgrove
    Discovery Sciences Computational Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
    J Chem Inf Model 52:1936-47. 2012
    ....
  17. doi request reprint Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes
    William McCoull
    Cardiovascular and Gastrointestinal Innovative Medicines Unit, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
    Bioorg Med Chem Lett 22:3873-8. 2012
    ..6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship...
  18. doi request reprint Theoretical prediction of a perepoxide intermediate for the reaction of singlet oxygen with trans-cyclooctene contrasts with the two-step no-intermediate ene reaction for acyclic alkenes
    Andrew G Leach
    AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, UK
    J Org Chem 73:8511-9. 2008
    ..The perepoxide is formed through a polarized diradical intermediate that can lead to the observation of alkene isomerization. The polarized diradical also becomes a minimum because of the barrier to abstraction...
  19. ncbi request reprint Inhibitors of epidermal growth factor receptor tyrosine kinase: Novel C-5 substituted anilinoquinazolines designed to target the ribose pocket
    Peter Ballard
    AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
    Bioorg Med Chem Lett 16:1633-7. 2006
    ..In vivo pharmacokinetics and disease model activity are discussed...
  20. ncbi request reprint Theoretical investigation of the origins of catalysis of a retro-Diels-Alder reaction by antibody 10F11
    Andrew G Leach
    AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
    J Org Chem 69:3683-92. 2004
    ..Reymond's studies suggest that the hydrogen-bonding network may be mediated through a water molecule in the binding site...
  21. ncbi request reprint Antibody-catalyzed oxy-cope rearrangement: mechanism and origins of catalysis and stereoselectivity from DFT quantum mechanics and flexible docking
    Kersey A Black
    Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095 1569, USA
    J Am Chem Soc 126:9695-708. 2004
    ..Docking studies also predict the S stereoselectivity of mature AZ28 and suggest that binding modes quite different from those of the hapten might play a role in catalysis, with specific focus on ligand hydrogen bonding to Asp(H101)...
  22. ncbi request reprint The origins of noncovalent catalysis of intermolecular Diels-Alder reactions by cyclodextrins, self-assembling capsules, antibodies, and RNAses
    Susanna P Kim
    Department of Chemistry and Biochemistry, University of California, Los Angeles 90095 1569, USA
    J Org Chem 67:4250-60. 2002
    ..None of the hosts achieve significant specific binding of transition states that is the hallmark of enzyme catalysis...