Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-06-02
1998-02-17
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 16, 514 18, 530329, 530330, C07K 702, C07K 704, A61K 3800, A61K 3808
Patent
active
057191280
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to certain medicinal compounds and their use as anti-factor IIa inhibitors.
BACKGROUND ART
Attempts have been made in the past to make efficacious anticoagulants. One type of anticoagulant acts to prevent the production of fibrin by somehow preventing the production of an enzyme called thrombin ("factor IIa"). This is done since thrombin acts to catalyze the cleavage of fibrinogen to form fibrin, the material from which blood clots are formed.
For example, U.S. Pat. No. 4,857,508 describes certain "RGD" peptide derivatives which assertedly inhibit platelet aggregation. These peptide derivatives are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gpIIb/IIIa receptor.
A class of bivalent peptide inhibitors of thrombin is described in Biochemistry 29, 7095-7101, 1990. These peptides, called "hirulogs", contain the active site inhibitory sequence H-D-Phe-Pro-Arg-Pro- which is linked at the C-terminus, via a spacer of a variable number of glycyl residues, to a dodecapeptide derived from hirudin, a natural thrombin inhibitor. The dodecapeptide sequence is capable of binding to the anion-binding exosite of thrombin.
U.S. Pat. Nos. 4,638,047 and 4,772,686 to Szelke et al describe certain peptides (modified partial sequences of human fibrinogen) wherein an amide bond, especially the one that corresponds to the scissile Arg.sup.16 --Gly.sup.17 of fibrinogen, is replaced by a nonhydrolyzable isosteric linkage. These compounds are assertedly useful as thrombin inhibitors, and have the formula: W could be hydrogen, Y could be D-Phe, Z could be L-Pro, A could be a keto dipeptide, and have a high binding activity for thrombin.
SUMMARY OF THE INVENTION
Surprisingly it has been found that by making certain modifications to the "Pro-Arg" portion of the prior art compounds, reversible, highly potent, highly selective factor IIa inhibitors useful in inhibiting the production of fibrin are produced.
The invention thus includes compounds of the formula:
In this compound, X may be hydrogen, CH.sub.3, an acyl group, or a general protective group (e.g. Boc, Z, or derivatives thereof).
Y is D-Phe, D-diphenylalanyl, D-Val, D-Ile, or D-Nle.
Z may be L-Ala, L-Val, L-Leu or L-Pro.
A may be ##STR1## wherein M is --(CO).sub.d --NH--, --CO--CH.sub.2 -- or --COCF.sub.2 --, d is 1 or 2. R.sup.1 is an amino acid side chain that is characteristic of a hydrophobic, basic amino acid with an aliphatic or aromatic chain or spacer. R.sup.2 may be hydrogen, methyl, or hydroxymethylene.
P is a substituted or unsubstituted amino acid selected from the group consisting of L/D-Phe (e.g. including p-chlorophenylalanyl ("pClPhe"), homo-Phe ("HPhe") and L/D-Tyr), L/D-cyclohexylalanyl, L/D-naphthylalanyl (1), L/D-naphthylalanyl (2) , L/D-.alpha.MePhe, L/D-phenylglycyl, L/D-.alpha.MeTyr, L/D-Leu, L/D-Ile, L/D-Nle, L/D-Arg, L/D-Lys or L/D-His.
Q, when present, is selected from the group consisting of L/D-Arg, L/D-Lys, pipecolic acid (Pec), L/D-Nle and L/D-Tyr.
T may be --OH, --OR.sup.4, --NR.sup.4 R.sup.5 or --N(CH.sub.2).sub.1-6 NR.sup.4 R.sup.5, wherein R.sup.4 and R.sup.5 are independently selected from hydrogen, alkyl, aryl, and aralkyl, or wherein R.sup.4 and R.sup.5 together with the nitrogen atom to which they are bonded may form a ring.
Due to their anti-factor IIa activity, these compounds have use in the manufacture of anticoagulant medicaments, especially ones intended for acute or initial administration. Once manufactured, the medicaments may be used in the treatment of mammals, including man. The medicaments are administered, on a regular basis, for example continually, to a mammal, believed to be suffering from a disease state susceptible to treatment by such medicaments. Such disease states include pulmonary embolism, thrombophlebitis, and arterial occlusion from thrombosis or embolism.
These compounds may also be used prophylactically to prevent further embolism, to forestall arterial and venous thrombosis, to prevent thromboemb
REFERENCES:
patent: 4318904 (1982-03-01), Shaw et al.
J.M. Maraganore, "Design and Characterization of Hirulogs: A Novel Class of Bivalent Peptide Inhibitors of Thrombin," Biochemistry, vol. 29, No. 30, pp.7095-7101, Jul. 1990, Easton, PA, USA.
K. Krupinski, "Antithrombotic Effects of Three Inhibitors in a Rat Model of Laser-Induced Thrombosis," Haemostasis, vol. 19, No. 2, pp. 74-82, 1989.
T. Kline, "Hirulog Peptides with Scissle Bond Replacements Resistant to Thrombin Cleavage," Biocheical and Biophysical Research Communications, vol. 177, No. 3, pp. 1049-1055, Jun. 28, 1991, USA.
Jetten Wilhelmientje
Ottenheym Henricus Carl Joseph
Peters Jacobus Albertus Maria
Van Nispen Johannes Wilhelmus Franciscus Maria
Visser Arie
Akzo Nobel N.V.
Borin Michael
Gormley Mary E.
Tsang Cecilia J.
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