Tags

Type your tag names separated by a space and hit enter

Structure-based design of residue 1 analogs of the direct thrombin inhibitor pentapeptide FM 19.
Chem Biol Drug Des. 2010 Jan; 75(1):35-9.CB

Abstract

Myocardial ischemia and other acute coronary syndromes are leading causes of death worldwide, and often result from a thrombus that blocks an atherosclerotic coronary artery. A key enzyme in thrombus formation is the serine protease thrombin, which is responsible for both the conversion of soluble fibrinogen into insoluble fibrin, as well as the activation of the GPCRs, PAR1 and PAR4, which stimulate platelet aggregation. Thus, thrombin is an attractive target for anticoagulant and antithrombotic therapy. Previous studies in our laboratory led to the development of lead compound FM 19 (D-Arg-Oic-Pro-D-Ala-Phe(p-Me)-NH2), which shows modest potency as a thrombin inhibitor. The recently determined X-ray structure of FM 19 in the active site of thrombin has revealed potential sites for modification to improve potency. This study reports replacements to the first residue (D-Arg1) of FM 19, which seek to improve potency by removing the N-terminal amine to eliminate an adverse electrostatic interaction, and alterations to the length of the side chain to eliminate an unfavorable eclipsed conformation observed in the X-ray structure. This study produced two compounds, 1 and 9, with improved alpha-thrombin inhibition (IC50 values of 0.66 +/- 0.20 microM and 0.57 +/- 0.12 microM, respectively).

Authors+Show Affiliations

Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19954432

Citation

Girnys, Elizabeth A., et al. "Structure-based Design of Residue 1 Analogs of the Direct Thrombin Inhibitor Pentapeptide FM 19." Chemical Biology & Drug Design, vol. 75, no. 1, 2010, pp. 35-9.
Girnys EA, Sobczyk-Kojiro K, Mosberg HI. Structure-based design of residue 1 analogs of the direct thrombin inhibitor pentapeptide FM 19. Chem Biol Drug Des. 2010;75(1):35-9.
Girnys, E. A., Sobczyk-Kojiro, K., & Mosberg, H. I. (2010). Structure-based design of residue 1 analogs of the direct thrombin inhibitor pentapeptide FM 19. Chemical Biology & Drug Design, 75(1), 35-9. https://doi.org/10.1111/j.1747-0285.2009.00915.x
Girnys EA, Sobczyk-Kojiro K, Mosberg HI. Structure-based Design of Residue 1 Analogs of the Direct Thrombin Inhibitor Pentapeptide FM 19. Chem Biol Drug Des. 2010;75(1):35-9. PubMed PMID: 19954432.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure-based design of residue 1 analogs of the direct thrombin inhibitor pentapeptide FM 19. AU - Girnys,Elizabeth A, AU - Sobczyk-Kojiro,Katarzyna, AU - Mosberg,Henry I, PY - 2009/12/4/entrez PY - 2009/12/4/pubmed PY - 2010/4/28/medline SP - 35 EP - 9 JF - Chemical biology & drug design JO - Chem Biol Drug Des VL - 75 IS - 1 N2 - Myocardial ischemia and other acute coronary syndromes are leading causes of death worldwide, and often result from a thrombus that blocks an atherosclerotic coronary artery. A key enzyme in thrombus formation is the serine protease thrombin, which is responsible for both the conversion of soluble fibrinogen into insoluble fibrin, as well as the activation of the GPCRs, PAR1 and PAR4, which stimulate platelet aggregation. Thus, thrombin is an attractive target for anticoagulant and antithrombotic therapy. Previous studies in our laboratory led to the development of lead compound FM 19 (D-Arg-Oic-Pro-D-Ala-Phe(p-Me)-NH2), which shows modest potency as a thrombin inhibitor. The recently determined X-ray structure of FM 19 in the active site of thrombin has revealed potential sites for modification to improve potency. This study reports replacements to the first residue (D-Arg1) of FM 19, which seek to improve potency by removing the N-terminal amine to eliminate an adverse electrostatic interaction, and alterations to the length of the side chain to eliminate an unfavorable eclipsed conformation observed in the X-ray structure. This study produced two compounds, 1 and 9, with improved alpha-thrombin inhibition (IC50 values of 0.66 +/- 0.20 microM and 0.57 +/- 0.12 microM, respectively). SN - 1747-0285 UR - https://www.unboundmedicine.com/medline/citation/19954432/Structure_based_design_of_residue_1_analogs_of_the_direct_thrombin_inhibitor_pentapeptide_FM_19_ L2 - https://doi.org/10.1111/j.1747-0285.2009.00915.x DB - PRIME DP - Unbound Medicine ER -