Máire A Convery

Publications (12)33.92 Total impact

• Article: The discovery of potent and long-acting oral factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs.

  Nigel S Watson, Carl Adams, David Belton, David Brown, Cynthia L Burns-Kurtis, Laiq Chaudry, Chuen Chan, Máire A Convery, David E Davies, Anne M Exall, [......], Anthony J Pateman, Angela N Patikis, Theresa J Roethke, Stefan Senger, Gary J Stelman, John R Toomey, Robert I West, Caroline Whittaker, Ping Zhou, Robert J Young
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  ABSTRACT: The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust candidate for progression towards clinical studies.
  Bioorganic & medicinal chemistry letters 02/2011; 21(6):1588-92. · 2.65 Impact Factor
• Article: Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs.

  Robert J Young, Carl Adams, Mike Blows, David Brown, Cynthia L Burns-Kurtis, Chuen Chan, Laiq Chaudry, Máire A Convery, David E Davies, Anne M Exall, [......], Anthony J Pateman, Angela N Patikis, Theresa J Roethka, Stefan Senger, Gary J Stelman, John R Toomey, Robert I West, Caroline Whittaker, Ping Zhou, Nigel S Watson
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  ABSTRACT: The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.
  Bioorganic & medicinal chemistry letters 02/2011; 21(6):1582-7. · 2.65 Impact Factor
• Article: Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.

  Savvas Kleanthous, Alan D Borthwick, David Brown, Cynthia L Burns-Kurtis, Matthew Campbell, Laiq Chaudry, Chuen Chan, Marie-Olive Clarte, Máire A Convery, John D Harling, [......], Theresa J Roethka, Stefan Senger, Gita P Shah, Gary J Stelman, John R Toomey, Nigel S Watson, Robert I West, Caroline Whittaker, Ping Zhou, Robert J Young
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  ABSTRACT: Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.
  Bioorganic & medicinal chemistry letters 11/2009; 20(2):618-22. · 2.65 Impact Factor
• Article: The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors.

  Ian P Holmes, Simon Gaines, Steve P Watson, Olivier Lorthioir, Adam Walker, Suzanne J Baddeley, Shane Herbert, Danielle Egan, Máire A Convery, Onkar M P Singh, Jeffrey W Gross, John M Strelow, Robert H Smith, Augustin J Amour, David Brown, Stephen L Martin
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  ABSTRACT: A new class of selective MMP-12 inhibitors have been identified via high throughput screening. Crystallization with MMP-12 confirmed the mode of binding and allowed initial optimization to be carried out using classical structure based design.
  Bioorganic & medicinal chemistry letters 09/2009; 19(19):5760-3. · 2.65 Impact Factor
• Article: Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs.

  Robert J Young, Alan D Borthwick, David Brown, Cynthia L Burns-Kurtis, Matthew Campbell, Chuen Chan, Marie Charbaut, Chun-wa Chung, Máire A Convery, Henry A Kelly, [......], Andrew M Mason, Anthony J Pateman, Angela N Patikis, Ivan L Pinto, Derek R Pollard, Stefan Senger, Gita P Shah, John R Toomey, Nigel S Watson, Helen E Weston
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  ABSTRACT: Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.
  Bioorganic & medicinal chemistry letters 02/2008; 18(1):23-7. · 2.65 Impact Factor
• Article: Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.

  Robert J Young, Alan D Borthwick, David Brown, Cynthia L Burns-Kurtis, Matthew Campbell, Chuen Chan, Marie Charbaut, Máire A Convery, Hawa Diallo, Eric Hortense, [......], Anthony J Pateman, Angela N Patikis, Ivan L Pinto, Derek R Pollard, Stefan Senger, Gita P Shah, John R Toomey, Nigel S Watson, Helen E Weston, Ping Zhou
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  ABSTRACT: Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
  Bioorganic & medicinal chemistry letters 02/2008; 18(1):28-33. · 2.65 Impact Factor
• Article: Sulfonamide-related conformational effects and their importance in structure-based design.

  Stefan Senger, Chuen Chan, Máire A Convery, Julia A Hubbard, Gita P Shah, Nigel S Watson, Robert J Young
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  ABSTRACT: Structure-based design (SBD) is a challenging endeavour since even localised SAR can hardly ever be explained by the variation of just one dominating factor. Here, we present a rare example where structural information combined with ab initio calculations clearly indicate that the observed difference in biological activity is dominated by conformational effects. The learnings discussed are successfully put to the test and have the potential to be of general use as a qualitative guide in SBD efforts.
  Bioorganic & Medicinal Chemistry Letters 06/2007; 17(10):2931-4. · 2.55 Impact Factor
• Article: Selective and dual action orally active inhibitors of thrombin and factor Xa.

  Robert J Young, David Brown, Cynthia L Burns-Kurtis, Chuen Chan, Máire A Convery, Julia A Hubbard, Henry A Kelly, Anthony J Pateman, Angela Patikis, Stefan Senger, Gita P Shah, John R Toomey, Nigel S Watson, Ping Zhou
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  ABSTRACT: The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.
  Bioorganic & Medicinal Chemistry Letters 06/2007; 17(10):2927-30. · 2.55 Impact Factor
• Article: Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.

  Chuen Chan, Alan D Borthwick, David Brown, Cynthia L Burns-Kurtis, Matthew Campbell, Laiq Chaudry, Chun-wa Chung, Máire A Convery, J Nicole Hamblin, Lisa Johnstone, [......], Champa Patel, Anthony J Pateman, Stefan Senger, Gita P Shah, John R Toomey, Nigel S Watson, Helen E Weston, Caroline Whitworth, Robert J Young, Ping Zhou
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  ABSTRACT: Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.
  Journal of Medicinal Chemistry 05/2007; 50(7):1546-57. · 5.25 Impact Factor
• Article: Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.

  Robert J Young, Matthew Campbell, Alan D Borthwick, David Brown, Cynthia L Burns-Kurtis, Chuen Chan, Máire A Convery, Miriam C Crowe, Satish Dayal, Hawa Diallo, [......], Andrew M Mason, Jackie E Mordaunt, Champa Patel, Anthony J Pateman, Stefan Senger, Gita P Shah, Paul W Smith, Nigel S Watson, Helen E Weston, Ping Zhou
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  ABSTRACT: Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.
  Bioorganic & Medicinal Chemistry Letters 01/2007; 16(23):5953-7. · 2.55 Impact Factor
• Article: Arylsulfonamides: a study of the relationship between activity and conformational preferences for a series of factor Xa inhibitors.

  Stefan Senger, Máire A Convery, Chuen Chan, Nigel S Watson
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  ABSTRACT: Torsional scans of sulfonamide S-C bonds in small model systems of a series of arylsulfonamide factor Xa inhibitors were performed in order to investigate if conformational effects can help to rationalise the observed SAR. Computational results were in good agreement with the experimental data indicating that the sulfonamide conformation plays an important role in determining the activity in this particular series of factor Xa inhibitors.
  Bioorganic & Medicinal Chemistry Letters 12/2006; 16(22):5731-5. · 2.55 Impact Factor
• Article: Design and synthesis of orally active pyrrolidin-2-one-based factor Xa inhibitors.

  Nigel S Watson, David Brown, Matthew Campbell, Chuen Chan, Laiq Chaudry, Máire A Convery, Rebecca Fenwick, J Nicole Hamblin, Claudine Haslam, Henry A Kelly, [......], Gary R Manchee, Andrew M Mason, Charlotte Mitchell, Champa Patel, Vipulkumar K Patel, Stefan Senger, Gita P Shah, Helen E Weston, Caroline Whitworth, Robert J Young
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  ABSTRACT: A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.
  Bioorganic & Medicinal Chemistry Letters 08/2006; 16(14):3784-8. · 2.55 Impact Factor