Di-, tri-, and tetra-peptides having antiangiogenic activity
View Patent ↗Compounds having the formula (SEQ ID NO:1), which are useful for treating conditions that arise from or are exacerbated by angiogenesis, are described. Also disclosed are pharmaceutical compositions comprising these compounds, methods of treatment using these compounds, and methods of inhibiting angiogenesis.
1. The compound of formula (I)
Xaa1-Xaa2-Xaa3-Xaa4-Xaa5(SEQ ID NO:1) (I),
or therapeutically acceptable salt thereof, wherein
Xaa 1 is R—(CH 2 ) n —C(O)—;
n is 0;
R is selected from the group consisting of alkyl and heterocycle, wherein the alkyl is selected from the group consisting of methyl and n-butyl, and wherein the heterocycle is 6-methylpyridinyl;
Xaa 2 is selected from the group consisting of D-alanyl, arginyl, asparaginyl, aspartyl, citrullyl, glutaminyl, histidyl, isoleucyl, D-isoleucyl, D-leucyl, D-lysyl(N-epsilon acetyl) lysyl(N-epsilon acetyl), lysyl(N-epsilon-nicotinyl), methionyl, norleucyl, ornithyl, prolyl, homoseryl, seryl, allothreonyl, and threonyl;
Xaa 3 is selected from the group consisting of arginyl and citrullyl;
Xaa 4 is absent or prolyl; and
Xaa 5 is selected from the group consisting of D-alanylamide, —NHCH 2 CH 3 , and —NHCH(CH 3 ) 2 .
2. The compound of claim 1 wherein Xaa 3 is arginyl.
3. The compound of claim 1 wherein Xaa 2 is isoleucyl.
4. The compound of claim 2 selected from the group consisting of
N-Ac-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-(6-methylnicotinyl)-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Ile-Arg-Pro-NHCH(CH 3 ) 2 ;
N-Ac-Ile-Arg-Pro-D-AlaNH 2 ;
N-Ac-Ile-Arg-NHCH 2 CH 3 ;
N-Ac-Ile-Arg-NHCH(CH 3 ) 2 ; and
N-(6-Me-nicotinyl)-Ile-Arg-NHCH 2 CH 3 .
5. The compound of claim 1 wherein Xaa 2 is D-isoleucyl.
6. The compound of claim 4 selected from the group consisting of
N-(6-methylnicotinyl)-D-Ile-Arg-Pro-NHCH 2 CH 3 ; and
N-Ac-D-Ile-Arg-Pro-NHCH 2 CH 3 .
7. The compound of claim 1 wherein Xaa 2 is selected from the group consisting of prolyl, D-lysyl(N-epsilon acetyl), lysyl(N-epsilon acetyl), and lysyl(N-epsilon-nicotinyl).
8. The compound of claim 6 selected from the group consisting of
N-Ac-Pro-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-D-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Lys(Ac)-Arg-NHCH 2 CH 3 ;
N-Ac-Lys(Nic)-Arg-NHCH 2 CH 3 ;
N-(6-Me-nicotinyl)-Lys(Ac)-Arg-NHCH 2 CH 3 ; and
N-Ac-Lys(Ac)-Arg-Pro-D-AlaNH 2 .
9. The compound of claim 1 wherein Xaa 2 is selected from the group consisting of D-alanyl, citrullyl, and D-leucyl.
10. The compound of claim 8 selected from the group consisting of
N-Ac-D-Ala-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-D-Leu-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Cit-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Cit-Arg-NHCH 2 CH 3 ; and
N-Ac-Cit-Arg-Pro-D-AlaNH 2 .
11. The compound of claim 1 wherein Xaa 2 is selected from the group consisting of arginyl, asparaginyl, methionyl, norleucyl, ornithyl, aspartyl, glutaminyl, homoseryl, histidyl, seryl, allothreonyl, and threonyl.
12. The compound of claim 10 selected from the group consisting of
N-Ac-Thr-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Ser-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Nle-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Orn-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Asp-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Gln-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Asn-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Met-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Hser-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-alloThr-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-His-Arg-Pro-NHCH 2 CH 3 ; and
N-Ac-alloTHr-Arg-Pro-D-AlaNH 2 .
13. The compound of claim 1 wherein Xaa 3 is citrullyl.
14. The compound of claim 13 wherein Xaa 2 is selected from the group consisting of arginyl and lysyl(N-epsilon acetyl).
15. The compound of claim 13 selected from the group consisting of
N-Ac-Arg-Cit-Pro-NHCH 2 CH 3 ; and
N-Ac-Lys(Ac)-Cit-NHCH 2 CH 3 .
16. A composition comprising a compound of claim 1 , or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.