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Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2.
J Med Chem. 1999 Jul 29; 42(15):2760-73.JM

Abstract

Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for thrombin activation. Herein we report a series of isoxazoline derivatives which are potent FXa inhibitors. Optimization of the side chain at the quaternary position of the isoxazoline ring led to SK549 which showed subnanomolar FXa potency (K(i) 0.52 nM). SK549 shows good selectivity for FXa compared to thrombin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series.

Authors+Show Affiliations

DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10425087

Citation

Quan, M L., et al. "Design and Synthesis of Isoxazoline Derivatives as Factor Xa Inhibitors. 2." Journal of Medicinal Chemistry, vol. 42, no. 15, 1999, pp. 2760-73.
Quan ML, Ellis CD, Liauw AY, et al. Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2. J Med Chem. 1999;42(15):2760-73.
Quan, M. L., Ellis, C. D., Liauw, A. Y., Alexander, R. S., Knabb, R. M., Lam, G., Wright, M. R., Wong, P. C., & Wexler, R. R. (1999). Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2. Journal of Medicinal Chemistry, 42(15), 2760-73.
Quan ML, et al. Design and Synthesis of Isoxazoline Derivatives as Factor Xa Inhibitors. 2. J Med Chem. 1999 Jul 29;42(15):2760-73. PubMed PMID: 10425087.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2. AU - Quan,M L, AU - Ellis,C D, AU - Liauw,A Y, AU - Alexander,R S, AU - Knabb,R M, AU - Lam,G, AU - Wright,M R, AU - Wong,P C, AU - Wexler,R R, PY - 1999/7/30/pubmed PY - 1999/7/30/medline PY - 1999/7/30/entrez SP - 2760 EP - 73 JF - Journal of medicinal chemistry JO - J Med Chem VL - 42 IS - 15 N2 - Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for thrombin activation. Herein we report a series of isoxazoline derivatives which are potent FXa inhibitors. Optimization of the side chain at the quaternary position of the isoxazoline ring led to SK549 which showed subnanomolar FXa potency (K(i) 0.52 nM). SK549 shows good selectivity for FXa compared to thrombin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/10425087/Design_and_synthesis_of_isoxazoline_derivatives_as_factor_Xa_inhibitors__2_ L2 - https://doi.org/10.1021/jm980406a DB - PRIME DP - Unbound Medicine ER -