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39 results on '"Bhakta C"'

36. Design and synthesis of factor Xa inhibitors and their prodrugs.

Author

Song Y, Clizbe L, Bhakta C, Teng W, Wong P, Huang B, Tran K, Sinha U, Park G, Reed A, Scarborough RM, and Zhu BY

Subjects
Amidines chemical synthesis, Amidines pharmacology, Animals, Biological Availability, Dogs, Drug Design, Prodrugs pharmacology, Rats, Structure-Activity Relationship, Factor Xa Inhibitors, Prodrugs chemical synthesis, Serine Proteinase Inhibitors chemical synthesis, Serine Proteinase Inhibitors pharmacology
Abstract

In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency (14, IC(50)=0.028 microM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.

Published
2003
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37. Substituted acrylamides as factor Xa inhibitors: improving bioavailability by P1 modification.

Author

Song Y, Clizbe L, Bhakta C, Teng W, Li W, Wong P, Huang B, Sinha U, Park G, Reed A, Scarborough RM, and Zhu BY

Subjects
Animals, Asparagine chemistry, Benzamidines chemistry, Biological Availability, Dogs, Half-Life, Hydrocarbons, Halogenated chemistry, Inhibitory Concentration 50, Isoquinolines chemical synthesis, Isoquinolines chemistry, Isoquinolines pharmacokinetics, Prothrombin Time, Rabbits, Rats, Stereoisomerism, Structure-Activity Relationship, Thrombin antagonists & inhibitors, Trypsin drug effects, Acrylamides chemistry, Acrylamides pharmacokinetics, Antithrombin III chemical synthesis, Antithrombin III pharmacokinetics, Factor Xa Inhibitors
Abstract

To overcome the low bioavailability of our substituted acrylamide P1 benzamidine factor Xa inhibitors reported previously, neutral and less basic groups were used to replace the benzamidine. As a result, a series of P1 aminoisoquinoline substituted acrylamide Xa inhibitors was identified to be potent, selective, and orally bioavailable. Modification of P4 moiety of these compounds further improved their pharmacokinetic properties.

Published
2002
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38. Design, synthesis, and SAR of substituted acrylamides as factor Xa inhibitors.

Author

Song Y, Clizbe L, Bhakta C, Teng W, Li W, Wu Y, Jia ZJ, Zhang P, Wang L, Doughan B, Su T, Kanter J, Woolfrey J, Wong P, Huang B, Tran K, Sinha U, Park G, Reed A, Malinowski J, Hollenbach S, Scarborough RM, and Zhu BY

Subjects
Acrylamides chemistry, Animals, Antithrombin III chemistry, Binding Sites, Biological Availability, Disease Models, Animal, Drug Design, Ligands, Models, Molecular, Rabbits, Rats, Stereoisomerism, Structure-Activity Relationship, Templates, Genetic, Thrombosis drug therapy, Acrylamides chemical synthesis, Acrylamides pharmacology, Antithrombin III chemical synthesis, Antithrombin III pharmacology, Factor Xa Inhibitors
Abstract

Substituted acrylamides were used as templates that bridge P1 and P4 binding elements, resulting in a series of potent (sub-nanomolar) and selective factor Xa inhibitors. In this template, cis-geometry of P1 and P4 ligands is highly preferred. SAR on the substituting groups, as well as on modification of P1 and P4 moieties is described. Compounds in this series show good in vivo efficacy in animal models.

Published
2002
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