POSITIVE MODULATOR OF BONE MORPHOGENIC PROTEIN-2

摘要

Compounds of the present invention of formula I and formula II are disclosed in the specification and wherein the compounds are modulators of Bone Morphogenic Protein activity. Compounds are synthetic peptides having a non-growth factor heparin binding region, a linker, and sequences that bind specifically to a receptor for Bone Morphogenic Protein. Uses of compounds of the present invention in the treatment of bone lesions, degenerative joint disease and to enhance bone formation are disclosed.

主权项

1. A compound of formula: wherein:
X is a peptide chain that (i) has a minimum of three amino acid residues, (ii) has a maximum of about fifty amino acid residues, and (iii) binds specifically to a Bone Morphogenic Protein-2 receptor;R1 is independently hydrogen, such that the terminal group is NH2, an acyl group with a linear or branched C1 to C17 alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chain including an N-terminus NH2, NH3+, or NH group or a corresponding acylated derivative, or is amino acid, a dipeptide or a tripeptide with an N-terminus NH2, NH3+, or NH group;R2 is independently a trifunctional alpha amino acid residue, wherein X is covalently bonded through a side chain of R2;R3 is independently a linker comprising a chain from 0 to about 15 backbone atoms covalently bonded to R2;R4 is OH such that the terminal group is a carboxyl, NH2, an acyl group with a linear or branched C1 to C17 alkyl, aryl, heteroaryl, alkene, alkenyl or aralkyl chain including an N-terminus NH2, NH3+, or NH group or a corresponding acylated derivative, or NH—R1;Y is a linker comprising a chain from 0 to about 50 backbone atoms covalently bonded to R2 and Z; andZ is a non-signaling peptide chain that includes a heparin binding domain comprising an amino acid sequence that comprises (i) a minimum of one heparin binding motif, (ii) a maximum of about ten heparin binding motifs, and (iii) a maximum of about thirty amino acids.