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Your search keyword '"Pinto, Ivan L."' showing total 6 results
Start Over Author "Pinto, Ivan L." Journal bioorganic medicinal chemistry letters
6 results on '"Pinto, Ivan L."'

1. Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.

Author

Kleanthous S, Borthwick AD, Brown D, Burns-Kurtis CL, Campbell M, Chaudry L, Chan C, Clarte MO, Convery MA, Harling JD, Hortense E, Irving WR, Irvine S, Pateman AJ, Patikis AN, Pinto IL, Pollard DR, Roethka TJ, Senger S, Shah GP, Stelman GJ, Toomey JR, Watson NS, West RI, Whittaker C, Zhou P, and Young RJ

Subjects
Anticoagulants chemical synthesis, Anticoagulants pharmacology, Binding Sites, Computer Simulation, Crystallography, X-Ray, Drug Design, Factor X metabolism, Pyrrolidinones chemical synthesis, Pyrrolidinones pharmacology, Structure-Activity Relationship, Anticoagulants chemistry, Factor X antagonists & inhibitors, Pyrrolidinones chemistry
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., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Published
2010
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2. Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.

Author

Young RJ, Borthwick AD, Brown D, Burns-Kurtis CL, Campbell M, Chan C, Charbaut M, Convery MA, Diallo H, Hortense E, Irving WR, Kelly HA, King NP, Kleanthous S, Mason AM, Pateman AJ, Patikis AN, Pinto IL, Pollard DR, Senger S, Shah GP, Toomey JR, Watson NS, Weston HE, and Zhou P

Subjects
Animals, Anticoagulants chemistry, Anticoagulants pharmacokinetics, Anticoagulants pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacokinetics, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Hydrophobic and Hydrophilic Interactions, Male, Models, Molecular, Pyrrolidinones pharmacokinetics, Pyrrolidinones pharmacology, Rats, Rats, Sprague-Dawley, Serine Proteinase Inhibitors pharmacokinetics, Serine Proteinase Inhibitors pharmacology, Stereoisomerism, Structure-Activity Relationship, Bridged Bicyclo Compounds, Heterocyclic chemistry, Factor Xa Inhibitors, Pyrrolidinones chemistry, Serine Proteinase Inhibitors chemistry
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.

Published
2008
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3. Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs.

Author

Young RJ, Borthwick AD, Brown D, Burns-Kurtis CL, Campbell M, Chan C, Charbaut M, Chung CW, Convery MA, Kelly HA, Paul King N, Kleanthous S, Mason AM, Pateman AJ, Patikis AN, Pinto IL, Pollard DR, Senger S, Shah GP, Toomey JR, Watson NS, and Weston HE

Subjects
Animals, Anticoagulants chemistry, Anticoagulants pharmacokinetics, Anticoagulants pharmacology, Drug Design, Male, Models, Molecular, Pyrrolidinones pharmacokinetics, Rats, Rats, Sprague-Dawley, Serine Proteinase Inhibitors pharmacokinetics, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Factor Xa Inhibitors, Pyrrolidinones chemistry, Pyrrolidinones pharmacology, Serine Proteinase Inhibitors chemistry, Serine Proteinase Inhibitors pharmacology
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.

Published
2008
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4. The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2.

Author

Blackie JA, Bloomer JC, Brown MJ, Cheng HY, Hammond B, Hickey DM, Ife RJ, Leach CA, Lewis VA, Macphee CH, Milliner KJ, Moores KE, Pinto IL, Smith SA, Stansfield IG, Stanway SJ, Taylor MA, and Theobald CJ

Subjects
1-Alkyl-2-acetylglycerophosphocholine Esterase, Animals, Cytochrome P-450 CYP2D6 Inhibitors, Enzyme Inhibitors chemistry, Humans, In Vitro Techniques, Kinetics, Phospholipases A blood, Phospholipases A2, Pyrimidinones chemistry, Rabbits, Recombinant Proteins antagonists & inhibitors, Enzyme Inhibitors pharmacology, Phospholipases A antagonists & inhibitors, Pyrimidinones pharmacology
Abstract

Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.

Published
2003
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5. The discovery of SB-435495. A potent, orally active inhibitor of lipoprotein-associated phospholipase A(2) for evaluation in man.

Author

Blackie JA, Bloomer JC, Brown MJ, Cheng HY, Elliott RL, Hammond B, Hickey DM, Ife RJ, Leach CA, Lewis VA, Macphee CH, Milliner KJ, Moores KE, Pinto IL, Smith SA, Stansfield IG, Stanway SJ, Taylor MA, Theobald CJ, and Whittaker CM

Subjects
Administration, Oral, Animals, Biphenyl Compounds administration & dosage, Biphenyl Compounds chemistry, Biphenyl Compounds metabolism, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Humans, Phospholipases A metabolism, Pyrimidinones administration & dosage, Pyrimidinones chemistry, Pyrimidinones metabolism, Rabbits, Structure-Activity Relationship, Biphenyl Compounds pharmacology, Enzyme Inhibitors pharmacology, Lipoproteins metabolism, Phospholipases A antagonists & inhibitors, Pyrimidinones pharmacology
Abstract

The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.

Published
2002
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6. Potent, orally active inhibitors of lipoprotein-associated phospholipase A(2): 1-(biphenylmethylamidoalkyl)-pyrimidones.

Author

Boyd HF, Fell SC, Hickey DM, Ife RJ, Leach CA, Macphee CH, Milliner KJ, Pinto IL, Rawlings DA, Smith SA, Stansfield IG, Stanway SJ, Theobald CJ, and Whittaker CM

Subjects
1-Alkyl-2-acetylglycerophosphocholine Esterase, Administration, Oral, Animals, Drug Design, Drug Evaluation, Preclinical, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Humans, Inhibitory Concentration 50, Kinetics, Pyrimidinones chemical synthesis, Pyrimidinones chemistry, Rabbits, Structure-Activity Relationship, Phospholipases A antagonists & inhibitors, Pyrimidinones pharmacokinetics
Abstract

A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects.

Published
2002
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