Design, synthesis and structure-activity relationship of a series of arginine aldehyde factor Xa inhibitors. Part 1: structures based on the (D)-Arg-Gly-Arg tripeptide sequence.

A series of arginine aldehyde inhibitors was designed as transition state (TS) analogues based on the known factor Xa specific substrate Cbz-D-Arg-Gly-Arg-pNA. BnSO2-(D)Arg-Gly-Arg-H (20) was found to be the most potent and selective inhibitor of factor Xa and prothrombinase activity in this series.

[1]  Robert Huber,et al.  X-ray Structure of Active Site-inhibited Clotting Factor Xa , 1996, The Journal of Biological Chemistry.

[2]  Michael E. Johnson,et al.  Proposed cation‐π mediated binding by factor Xa: a novel enzymatic mechanism for molecular recognition , 1995, FEBS letters.

[3]  R. Nutt,et al.  Design, synthesis, and evolution of a novel, selective, and orally bioavailable class of thrombin inhibitors: P1-argininal derivatives incorporating P3-P4 lactam sulfonamide moieties. , 1996, Journal of medicinal chemistry.

[4]  P. Bartlett,et al.  Phosphonamidates as transition-state analogue inhibitors of thermolysin. , 1983, Biochemistry.

[5]  R. Scarborough.  Coagulation factor Xa: the prothrombinase complex as an emerging therapeutic target for small molecule inhibitors. , 1998, Journal of enzyme inhibition.

[6]  S. Bajusz,et al.  Inhibition of thrombin and trypsin by tripeptide aldehydes. , 2009, International journal of peptide and protein research.

[7]  A. Tulinsky,et al.  Highly selective mechanism-based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes. , 1998, Biochemistry.

[8]  R. Nutt,et al.  Rational design and synthesis of a novel, selective class of thrombin inhibitors: P1-argininal derivatives incorporating P3P4 quaternary lactam dipeptide surrogates , 1997 .

[9]  D. Gifford-Moore,et al.  Structure-activity study of tripeptide thrombin inhibitors using alpha-alkyl amino acids and other conformationally constrained amino acid substitutions. , 1995, Journal of medicinal chemistry.

[10]  J. Vacca,et al.  L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor. , 1998, Bioorganic & medicinal chemistry letters.

[11]  J. Edmunds,et al.  Chapter 6. Thrombin and Factor Xa Inhibition , 1996 .

[12]  S. Tamura,et al.  Automated synthesis of peptide C-terminal aldehydes , 1992 .

[13]  R. Scarborough.  Chapter 8. Anticoagulant Strategies Targeting Thrombin and Factor Xa , 1995 .