Peptide-compound cyclization method
An object of the present invention is to provide methods of discovering drugs effective for tough targets, which have conventionally been discovered only with difficulty. The present invention relates to novel methods for cyclizing peptide compounds, and novel peptide compounds and libraries comprising the same, to achieve the above object.
1. A peptide compound having a cyclic portion, wherein:
(i) the peptide compound contains a cyclic portion composed of 5 to 12 amino acids and amino acid analog residues in total, and has 9 to 13 amino acids and amino acid analogs in total,
(ii) the peptide compound contains at least three N-alkylated amino acids, wherein the N-alkylated amino acids are N-methylated amino acids,
(iii) the peptide compound has a ClogP value of 8 to 15, and
(iv) the peptide compound has at least one amide bond formed between a side chain of an amino acid or an amino acid analog and a nitrogen atom of the main chain of another amino acid or amino acid analog,
wherein the peptide compound comprises an amide bond formed between a side chain of an optionally substituted glutamic acid or an optionally substituted aspartic acid and a nitrogen atom of the main chain of another amino acid.
2. The peptide compound according to claim 1 , wherein the compound further comprises at least one linear portion composed of 1 to 8 amino acids and amino acid analog residues in total.
3. The peptide compound according to claim 2 , wherein the C-terminal site of the peptide is —CO—NRR′ wherein
R and R′ each independently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted aralkyl group, or
R and R′ form a ring.
4. The peptide compound according to claim 2 , wherein the cyclic portion includes an intersection unit represented by the following general formula (I):
wherein
R51 is —CO—NRR′ wherein
R and R′ each independently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted aralkyl group, or
R and R′ together form a ring,
R52 is a C1-C6 alkyl group, an aryl group or an aralkyl group which optionally has a substituent,
R53 is a C1-C6 alkyl group which optionally has a substituent, or a hydrogen atom, or
R53 and R51 optionally be bonded to each other to form a C3-C5 alkylene group and form a 5- to 7-membered ring containing a nitrogen atom,
and
represents a binding site in the cyclic portion.
5. The peptide compound according to claim 1 , wherein the C-terminal site of the peptide is CO—NRR′ wherein
R and R′ each independently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted aralkyl group, or
R and R′ form a ring.
6. The peptide compound according to claim 5 , wherein the peptide compound contains at least one N-unsubstituted amino acid.
7. The peptide compound according to claim 5 , wherein the peptide compound contains at least one N-unsubstituted amino acid, and wherein the compound further comprises at least one linear portion composed of 1 to 3 amino acids and amino acid analog residues in total.
8. The peptide compound according to claim 1 , wherein the cyclic portion includes an intersection unit represented by the following general formula (I):
wherein
R51 is CO—NRR′ wherein
R and R′ each independently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted aralkyl group, or R and R′ together form a ring,
R52 is a C1-C6 alkyl group, an aryl group or an aralkyl group which optionally has a substituent,
R53 is a C1-C6 alkyl group which optionally has a substituent, or a hydrogen atom, or
R53 and R51 optionally be bonded to each other to form a C3-C5 alkylene group and form a 5- to 7-membered ring containing a nitrogen atom,
and
represents a binding site in the cyclic portion.
9. The peptide compound according to claim 8 , wherein the peptide compound contains at least one N-unsubstituted amino acid.
10. The peptide compound according to claim 8 , wherein the peptide compound contains at least one N-unsubstituted amino acid, and wherein the compound further comprises at least one linear portion composed of 1 to 3 amino acids and amino acid analog residues in total.
11. The peptide compound according to claim 1 , wherein the compound further comprises at least one linear portion composed of 1 to 3 amino acids and amino acid analog residues in total.
12. The peptide compound according to claim 1 , wherein the peptide compound contains at least one N-unsubstituted amino acid.
13. A pharmaceutical composition comprising the peptide compound according to claim 1 .
14. The pharmaceutical composition according to claim 13 , wherein the pharmaceutical composition is an oral formulation.