Hexa-, hepta-, and octapeptides having antiangiogenic activity
View Patent ↗Compounds of 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. A compound of formula (I)
Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 (SEQ ID NO:1) (I),
or a therapeutically acceptable salt thereof, wherein
Xaa 1 is selected from the group consisting of hydrogen and R—(CH 2 ) n —C(O)—, wherein n is an integer from 0 to 8 and R is selected from the group consisting of alkoxy, alkyl, amino, aryl, carboxyl, cycloalkenyl, cycloalkyl, and heterocycle;
Xaa 2 is selected from the group consisting of alanyl, (1R,4S)-1-aminocyclopen-2-ene-4-carbonyl, asparaginyl, D-asparaginyl, t-butylglycyl, citrullyl, cyclohexylglycyl, glutaminyl, D-glutaminyl, glutamyl, glycyl, histidyl, isoleucyl, leucyl, lysyl(N-epsilon-acetyl), methionyl, norvalyl, phenylalanyl, prolyl, 3-(3-pyridyl)alanyl, homoseryl, seryl, thienylalanyl, threonyl, D-valyl, and valyl;
Xaa 3 is selected from the group consisting of D-alanyl, D-alloisoleucyl, D-allylglycyl, D-4-chlorophenylalanyl, D-citrullyl, D-3-cyanophenylalanyl, D-homophenylalanyl, D-homoseryl, isoleucyl, D-isoleucyl, D-leucyl, N-methyl-D-leucyl, D-norleucyl, D-norvalyl, D-penicillaminyl, D-phenylalanyl, D-prolyl, D-seryl, D-thienylalanyl, and D-threonyl;
Xaa 4 is selected from the group consisting of allothreonyl, aspartyl, glutaminyl, D-glutaminyl, N-methylglutaminyl, glycyl, histidyl, homoseryl, isoleucyl, lysyl(N-epsilon-acetyl), methionyl, D-norvalyl, N-methylnorvalyl, seryl, N-methylseryl, threonyl, D-threonyl, tryptyl, tyrosyl, tyrosyl(O-methyl), and N-methylvalyl;
Xaa 5 is selected from the group consisting of alanyl, N-methylalanyl, allothreonyl, arginyl, glutaminyl, glycyl, homoseryl, leucyl, lysyl(N-epsilon-acetyl), norleucyl, norvalyl, D-norvalyl, N-methylnorvalyl, octylglycyl, ornithyl(N-delta acetyl), 3-(3-pyridyl)alanyl, sarcosyl, seryl, N-methylseryl, threonyl, tryptyl, valyl, and N-methylvalyl;
Xaa 6 is selected from the group consisting of alanyl, alloisoleucyl, aspartyl, citrullyl, isoleucyl, D-isoleucyl, N-methylisoleucyl, leucyl, D-leucyl, lysyl(N-epsilon-acetyl), D-lysyl(N-epsilon-acetyl), norvalyl, phenylalanyl, prolyl, and D-prolyl;
Xaa 7 is citrully;
Xaa 8 is absent or selected from the group consisting of N-methyl-D-alanyl, 2-aminobutyryl, 2-aminoisobutyryl, D-glutaminyl, homoprolyl, hydroxyprolyl, leucyl, phenylalanyl, prolyl, D-prolyl, and D-valyl; and
Xaa 9 is selected from the group consisting of D-alanylamide, azaglycylamide, glycylamide, lysyl(N-epsilon-acetyl)amide, D-lysyl(N-epsilon-acetyl)amide, —NHCH(CH 3 ) 2 , a group represented by the formula —NH—(CH 2 ) n —CHR 1 R 2 , and a group represented by the formula —NHR 3 , wherein n is an integer from 0 to 8; R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkenyl, and cycloalkyl; R 2 is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocycle, and hydroxyl, with the proviso that when n is 0, R 2 is other than alkoxy or hydroxyl; and R 3 is selected from the group consisting of hydrogen, cycloalkenyl, cycloalkyl, and hydroxyl.
2. The compound of claim 1 wherein Xaa 9 is D-alanylamide.
3. The compound of claim 2 that is N-Ac-Val-D-Ile-Thr-Nva-Ile-Cit-Pro-D-AIaNH 2 .