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Your search keyword '"Hu, Huiyong"' showing total 6 results
Start Over Author "Hu, Huiyong" Topic factor viia
6 results on '"Hu, Huiyong"'

1. Potent 4-amino-5-azaindole factor VIIa inhibitors.

Author

Hu H, Kolesnikov A, Riggs JR, Wesson KE, Stephens R, Leahy EM, Shrader WD, Sprengeler PA, Green MJ, Sanford E, Nguyen M, Gjerstad E, Cabuslay R, and Young WB

Subjects
Factor VIIa metabolism, Indoles chemistry, Molecular Structure, Pyridines chemistry, Structure-Activity Relationship, Factor VIIa antagonists & inhibitors, Indoles chemical synthesis, Indoles pharmacology, Pyridines chemical synthesis, Pyridines pharmacology
Abstract

The 4-amino-5-azaindole as an amidino-benzimidazole replacement is described. A series of potent and selective analogs were discovered and showed desirable ex vivo efficacy as measured by PT.

Published
2006
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2. Efforts toward oral bioavailability in factor VIIa inhibitors.

Author

Vijaykumar D, Rai R, Shaghafi M, Ton T, Torkelson S, Leahy EM, Riggs JR, Hu H, Sprengeler PA, Shrader WD, O'Bryan C, Cabuslay R, Sanford E, Gjerstadt E, Liu L, Sukbuntherng J, and Young WB

Subjects
Administration, Oral, Animals, Biological Availability, Rats, Structure-Activity Relationship, Thrombin antagonists & inhibitors, Anticoagulants chemical synthesis, Anticoagulants pharmacology, Factor VIIa antagonists & inhibitors, Thrombosis drug therapy
Abstract

Efforts toward developing orally bioavailable factor VIIa inhibitors starting from parenteral lead compound 1 are described. SAR resulted in improved physicochemical properties, leading to enhanced oral absorption in rat.

Published
2006
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3. Novel 5-azaindole factor VIIa inhibitors.

Author

Riggs JR, Hu H, Kolesnikov A, Leahy EM, Wesson KE, Shrader WD, Vijaykumar D, Wahl TA, Tong Z, Sprengeler PA, Green MJ, Yu C, Katz BA, Sanford E, Nguyen M, Cabuslay R, and Young WB

Subjects
Aza Compounds chemistry, Crystallography, X-Ray, Factor VIIa chemistry, Factor VIIa metabolism, Indoles chemistry, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Aza Compounds chemical synthesis, Aza Compounds pharmacology, Factor VIIa antagonists & inhibitors, Indoles chemical synthesis, Indoles pharmacology
Abstract

The discovery and development of 5-azaindole factor VIIa inhibitors will be described.

Published
2006
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4. Factor VIIa inhibitors: improved pharmacokinetic parameters.

Author

Kolesnikov A, Rai R, Young WB, Mordenti J, Liu L, Torkelson S, Shrader WD, Leahy EM, Hu H, Gjerstad E, Janc J, Katz BA, and Sprengeler PA

Subjects
Animals, Drug Design, Half-Life, Humans, Molecular Structure, Structure-Activity Relationship, Anticoagulants pharmacokinetics, Blood Coagulation drug effects, Factor VIIa antagonists & inhibitors, Serine Proteinase Inhibitors pharmacokinetics
Abstract

Efforts to improve the potency and pharmacokinetic properties of small molecule factor VIIa inhibitors are described. Small structural modifications to existing leads allow the modulation of half-life and clearance, potentially making these compounds suitable candidates for drug development.

Published
2006
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5. Factor VIIa inhibitors: chemical optimization, preclinical pharmacokinetics, pharmacodynamics, and efficacy in an arterial baboon thrombosis model.

Author

Young WB, Mordenti J, Torkelson S, Shrader WD, Kolesnikov A, Rai R, Liu L, Hu H, Leahy EM, Green MJ, Sprengeler PA, Katz BA, Yu C, Janc JW, Elrod KC, Marzec UM, and Hanson SR

Subjects
Animals, Chromatography, High Pressure Liquid, Crystallography, X-Ray, Models, Molecular, Papio, Serine Proteinase Inhibitors chemistry, Serine Proteinase Inhibitors pharmacokinetics, Serine Proteinase Inhibitors therapeutic use, Factor VIIa antagonists & inhibitors, Models, Animal, Serine Proteinase Inhibitors pharmacology, Thrombosis drug therapy
Abstract

Highly selective and potent factor VIIa-tissue factor (fVIIa.TF) complex inhibitors were generated through structure-based design. The pharmacokinetic properties of an optimized analog (9) were characterized in several preclinical species, demonstrating pharmacokinetic characteristics suitable for once-a-day dosing in humans. Analog 9 inhibited platelet and fibrin deposition in a dose-dependent manner after intravenous administration in a baboon thrombosis model, and a pharmacodynamic concentration-response model was developed to describe the platelet deposition data. Results for heparin and enoxaparin (Lovenox) in the baboon model are also presented.

Published
2006
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6. Factor VIIa inhibitors: gaining selectivity within the trypsin family.

Author

Shrader WD, Kolesnikov A, Burgess-Henry J, Rai R, Hendrix J, Hu H, Torkelson S, Ton T, Young WB, Katz BA, Yu C, Tang J, Cabuslay R, Sanford E, Janc JW, and Sprengeler PA

Subjects
Binding Sites, Factor Xa Inhibitors, Humans, Hydrogen Bonding, Protein Binding, Prothrombin antagonists & inhibitors, Structure-Activity Relationship, Trypsin metabolism, Factor VIIa antagonists & inhibitors
Abstract

Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa.

Published
2006
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