Acylated 4-amidino- and -4-guanidinobenzylamines for inhibition of plasma kallikrein
The invention relates to the use of acylated 4-amidino- or 4-guanidinobenzylamine in accordance with the general formula I P4-P3-P2-P1 (I), where P4 is a monosubstituted or polysubstituted or unsubstituted benzylsulfonyl group, P3 is a monosubstituted or polysubstituted or unsubstituted, natural or unnatural α-amino acid or α-imino acid in the D configuration, P2 is a monosubstituted or polysubstituted or unsubstituted, natural or unnatural α-amino acid or α-imino acid in the L configuration, and P1 is a monosubstituted or polysubstituted or unsubstituted 4-amidino- or 4-guanidinobenzylamine group, for inhibiting plasma kallikrein (PK), factor XIa and factor XIIa, in particular for preventing the activation of coagulation at synthetic surfaces and for systemic administration as anticoagulants/antithrombotic agents, in particular for preventing the activation of coagulation at synthetic surfaces for the purpose of averting thromboembolic events.
1. A method of inhibiting plasma kallikrein and/or factor XIa and/or factor XIIa in-a patient having a condition selected from the group consisting of cardiac infarction, an embolism, deep leg vein thrombosis, unstable angina, complications as a consequence of angioplasty, disseminated intravascular coagulation, septic shock, allergies, postgastrectomy syndrome, and adult respiratory distress syndrome, said method comprising administering to said patient a compound of formula I:
P4-P3-P2-P1 (I),
wherein
P1 is unsubstituted 4-amidinobenzylamine; and
(1) P4 is unsubstituted benzylsulfonyl,
P3 is D-Ser or D-Ser(tBu), and
P2 is Asp, Glu, Gln, hGlu, Dap(Z), Lys(Z), Thr, Thr(Bzl), Ser, Ser(Bzl), hSer, Phe or hPhe;
(2) P4 is benzylsulfonyl substituted with 4-COON or 4-COOMe,
P3 is D-Ser, and
P2 is Ser;
(3) P4 is benzylsulfonyl substituted with 4-CN,
P3 is D-Ser, and
P2 is Pro;
(4) P4 is unsubstituted benzylsulfonyl,
P3 is D-Cha, and
P2 is Glu, Lys, or Lys(Z); or
(5) P4 is benzylsulfonyl substituted with 3-CN, 3-aminomethyl, or 3-(Glut-NHCH 2 ),
P3 is D-Cha, and
P2 is Pro;
wherein the sulfur atom of the benzylsulfonyl group of P4 is linked to the α-amino group of P3, the carbon atom of the carbonyl group of P3 is bonded to the α-amino group of P2 or, when P2 is hSer, to the β-amino group of P2, and
the nitrogen atom of benzylamine of P1 is linked to the C-terminal carbonyl group of P2.
2. The method of claim 1 , wherein P4 is unsubstituted benzylsulfonyl.
3. The method of claim 2 , wherein P3 is D-Ser.
4. The method of claim 3 , wherein P2 is hPhe.
5. The method of claim 1 , wherein said compound is administered enterally.
6. The method of claim 5 , wherein said compound is administered orally.
7. The method of claim 1 , wherein said compound is administered parenterally.
8. The method of claim 7 , wherein said compound is administered intraarterially, intravenously, intramuscularly, or subcutaneously.
9. The method of claim 1 , wherein said deep leg vein thrombosis follows a hip joint surgery or a knee joint replacement.
10. The method of claim 1 , wherein said angioplasty is percutaneous transluminal coronary angioplasty.