One-bead-two-compound macrocyclic library and methods of preparation and use
A one-bead-two-compound combinatorial synthesis technique provides libraries of macrocyclic peptidomimetic compounds and compositions with use as ligands for the Ephrin type-A receptor 2 (EphA2). The one-bead-two-compound technique and libraries of macrocyclic compounds are useful as research tools in drug discovery and/or to treat or prevent a range of diseases or disorders.
1. A compound of formula (I)
or a salt thereof, wherein:
R 1 , R 2 , R 3 , R 4 , R 1 ′, R 2 ′, and R 3 ′ are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -L 1 -G 1 , -L 1 -NH 2 , -L 1 -NH(C 1-4 alkyl), -L 1 -N(C 1-4 alkyl) 2 , -L 1 -C(O)OH, -L 1 -C(O)OC 1-4 alkyl, -L 1 -C(O)NH 2 , and -L 1 -C(O)NH(C 1-4 alkyl);
G is H or a solid support, the solid support being optionally substituted with a peptide sequence coding for R 1 , R 2 , R 3 , R 4 , R 1 ′, R 2 ′, and R 3 ′;
L 1 is a bond or a C 1-4 alkylene; and
G 1 is C 3-8 cycloalkyl, aryl, a 4- to 12-membered heterocyclyl, or a 5- to 12-membered heteroaryl, wherein G 1 is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halogen.
2. The compound of claim 1 , or salt thereof, wherein:
R 1 , R 2 , R 3 , R 4 , R 1 ′, R 2 ′, and R 3 ′ are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, -L 1 -G 1 , —C 1-4 alkylene-NH 2 , —C 1-4 alkylene-NH(C 1-4 alkyl), —C 1-4 alkylene-N(C 1-4 alkyl) 2 , —C 1-4 alkylene-C(O)OH, —C 1-4 alkylene-C(O)OC 1-4 alkyl, —C 1-4 alkylene-C(O)NH 2 , and —C 1-4 alkylene-C(O)NH(C 1-4 alkyl).
3. The compound of claim 1 , or salt thereof, wherein:
G 1 is C 3-8 cycloalkyl, phenyl, or a 4- to 12-membered heterocyclyl, wherein G 1 is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and halogen.
4. The compound of claim 1 , or a salt thereof, wherein:
R 1 is hydrogen, aryl, C 1-6 alkyl, or —C 1-4 alkylene-NH 2 ;
R 1 ′ is —C 1-4 alkylene-Nth or —C 1-4 alkylene-G 1 , where G 1 is C 3-8 cycloalkyl or aryl;
R 2 is —C 1-4 alkylene-C(O)OH, aryl, or C 1-6 alkyl;
R 2 ′ is —C 1-4 alkylene-NH 2 or —C 1-4 alkylene-G 1 , where G 1 is C 3-8 cycloalkyl, aryl, or a 4- to 12-membered heterocyclyl;
R 3 is hydrogen or —C 1-4 alkylene-C(O)OH;
R 3 ′ is —C 1-4 alkylene-NH 2 , —C 1-4 alkylene-C(O)OH, or —C 1-4 alkylene-G 1 , where G 1 is aryl or a 4-to 12-membered heterocyclyl; and
R 4 is hydrogen, C 1-6 alkyl, —C 1-4 alkylene-C(O)OH, or aryl.
5. The compound of claim 1 , or salt thereof, wherein:
R 1 is aryl;
R 1 ′ is —C 1-4 alkylene-C 3-8 cycloalkyl;
R 2 is —C 1-4 alkylene-C(O)OH;
R 2 ′ is —C 1-4 alkylene-G 1 , where G 1 is a 4- to 12-membered heterocyclyl;
R 3 is —C 1-4 alkylene-C(O)OH;
R 3 ′ is —C 1-4 alkylene-C(O)OH; and
R 4 is aryl.
6. A compound of claim 1 , wherein G is hydrogen.
7. The compound of claim 1 , wherein G is a solid support, the solid support being substituted with a peptide sequence coding for R 1 , R 2 , R 3 , R 4 , R 1 ′, R 2 ′, and R 3 ′.
8. The compound of claim 7 , wherein the solid support has an interior portion and an exterior portion, the peptide sequence being attached to the interior portion and the macrocyclic peptidomimetic portion of formula (I)
being attached to the exterior portion.
9. The compound of claim 8 , wherein the peptide sequence and the macrocyclic peptidomimetic portion of formula (I) are independently attached to amino groups located, respectively, on the interior portion and the exterior portion.
10. A library comprising a plurality of compounds of claim 1 .
11. The library of claim 10 , wherein the plurality of compounds have formula (II),
wherein:
is the solid support;
R 1 , R 2 , R 3 , R 4 , R 1 ′, R 2 ′, and R 3 ′ are as defined in claim 1 ;
X 1 is a peptide side chain that codes for R 4 ;
X 2 is a peptide side chain that codes for R 3 ;
X 3 is a peptide side chain that codes for R 2 ;
X 4 is a peptide side chain that codes for R 1 ;
Y 2 is a peptide side chain that codes for R 3 ′;
Y 3 is a peptide side chain that codes for R 2 ′; and
Y 4 is a peptide side chain that codes for R 1 ′.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.