Peptoid and synthetic oligomers, pharmaceutical compositions and methods of using same

摘要

Novel peptide/peptoid oligomers are disclosed that have a formula represented by the following formula Ia or Ib:;
The peptide/peptoid oligomers demonstrate the ability to inhibit fibrillization and oligomerization of Aβ and may be prepared as pharmaceutical compositions and used for the prevention or treatment of a variety of conditions in mammals, including humans, associated with Aβ oligomerization. The present peptidomimetic oligomers are particularly valuable for the treatment of subjects with AD.

主权项

1. A synthetic oligomer
(i) wherein the synthetic oligomer is
X-Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala-Y (SEQ ID NO: 28);or a salt thereof, and stereoisomers, isotopic variants and tautomers thereof; and wherein at least one and up to 35 amino acid residues are replaced with monomers independently selected from Nap, Nab, Nah, Ngb, Npm, Nnm, Ndp, Nip, Nib, Nmg, and Nchm; or (ii) wherein the synthetic oligomer is X-Gly-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Y (SEQ ID NO: 32); or a salt thereof, and stereoisomers, isotopic variants and tautomers thereof; and wherein at least one and up to 5 amino acid residues are replaced with monomers independently selected from Nap, Nab, Nah, Ngb, Npm, Nnm, Ndp, Nip, Nib, Nmg, and Nchm; or (iii) wherein the synthetic oligomer is X-Gly-Lys-Leu-Val-Phe-Phe-Ala-Glu-Y (SEQ ID NO: 33); or a salt thereof, and stereoisomers, isotopic variants and tautomers thereof; and wherein at least one and up to 4 amino acid residues are replaced with monomers independently selected from Nap, Nab, Nah, Ngb, Npm, Nnm, Ndp, Nip, Nib, Nmg, and Nchm; or (iv) wherein the synthetic oligomer is X-Gly-Lys-Leu-Val-Phe-Phe-Y (SEQ ID NO: 34); or a salt thereof, and stereoisomers, isotopic variants and tautomers thereof; and wherein at least one and up to 4 amino acid residues are replaced with monomers independently selected from Nap, Nab, Nah, Ngb, Npm, Nnm, Ndp, Nip, Nib, Nmg, and Nchm; and
wherein: Phe is phenylalanine or cyclohexylalanine; and provided that a) the monomer or monomers adjacent to Nmg are other than Gly, Nmg, Ser, Ile, or Tyr; and b) none of -Gly-residues is replaced with Nmg.