US 5,874,529 A · Conformationally constrained backbone cyclized peptide analogs

Abstract

Novel backbone cyclized peptide analogs are formed by means of bridging groups attached via the alpha nitrogens of amino acid derivatives to provide novel non-peptidic linkages. Novel building units disclosed are N.sup..alpha. (.omega.-functionalized)amino acids constructed to include a spacer and a terminal functional group. One or more of these N.sup..alpha. (.omega.-functionalized) amino acids are incorporated into a peptide sequence, preferably during solid phase peptide synthesis. The reactive terminal functional groups are protected by specific protecting groups that can be selectively removed to effect either backbone-to-backbone or backbone-to-side chain cyclizations. The invention is exemplified by backbone cyclized bradykinin antagonists having biological activity. Further embodiments of the invention are somatostatin analogs having one or two ring structures involving backbone cyclization.

Claims16

Dependent claims

A backbone cyclized bradykinin peptide analog having the general formula (I):

##STR42## wherein:
a and b each independently designates an integer from 1 to 8 or zero;
d, e, and f each independently designates an integer from 1 to 10;
(AA) designates an amino acid residue wherein the amino acid residues in each chain may be the same or different;
E represents a hydroxyl group, a carboxyl protecting group or an amino group, or the E group and CO terminus of the adjacent (AA).sub.f amino acid residue are CH.sub.2 --OH;
each of R, R', R" and R'" is independently hydrogen or an amino acid side-chain optionally bound with a specific protecting group;
and the lines designate a bridging group of the Formula:
--X--M--Y--W--Z-- (i);
or
--X--M--Z-- (ii)
wherein:
one line may be absent;
M and W are independently selected from the group consisting of disulfide, amide, thioether, thioester, imine, ether, and alkene;
and X, Y and Z are each independently selected from the group consisting of alkylene, substituted alkylene, arylene, homo- or hetero-cycloalkylene and substituted cycloalkylene.

11 more elements

A backbone cyclized bradykinin peptide analog, wherein the backbone is cyclized to a side-chain of an amino acid of the general Formula (II):

##STR43## wherein d, e and f each independently designates an integer from 1 to 10;
(AA) designates an amino acid residue wherein the amino acid residues in each chain may be the same or different;
E represents a hydroxyl group, a carboxyl protecting or an amino group, or the E group and CO terminus of the adjacent (AA).sub.f amino acid residue are CH.sub.2 --OH;
R is an amino acid side chain optionally bound with a specific protecting group;
and the line designates a bridging group of the Formula;
--X--M--Y--W--Z-- (i);
or
--X--M--Z-- (ii)
wherein M and W are independently selected from the group consisting of disulfide, amide, thioether, imine, ether, and alkene;
X, Y and Z are each independently selected from the group consisting of alkylene, substituted alkylene, arylene, cycloalkylene and substituted cycloalkylene.

7 more elements

Dependencies are inferred from the claim text.

Conformationally constrained backbone cyclized peptide analogs

Life of this patent

Conformationally constrained backbone cyclized peptide analogs

Life of this patent

Abstract

Claims16