| 摘要 |
The invention relates generally to compounds which are allosteric modulators {e.g., positive and negative allosteric modulators, and allosteric agonists) of the G protein coupled receptor for stromal derived factor 1 (SDF-I), also known as the CXCR4 receptor. The CXCR4 receptor compounds are derived from the intracellular loops and domains of the CXCR4 receptor. The invention also relates to the use of these CXCR4 receptor compounds and pharmaceutical compositions comprising the CXCR4 receptor compounds in the treatment of diseases and conditions associated with CXCR4 modulation such as bone marrow transplantation, chemosensitization, cancer, metastatic disease (e.g., cancer), auto-immune disease (e.g., rheumatoid arthritis), fibrosis disease (e.g., pulmonary), AIDS infection, cardiovascular disease, uveitis, inflammatory diseases, celiac disease HIV infection and stem cell-based regenerative medicine. |
| 主权项 |
1. A compound represented by Formula A-1:
T-L-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-R1; or a pharmaceutically acceptable salt thereof, wherein: L is a linking moiety selected from: C(O), C(S), S(O)2, N(R3)S*(O), N(R3)S*(O)2, N(R3)C*(O), N(R3)C*(S), OC*(O), OC*(S), SC*(O), SC*(S), C(═NH), and N(R3)C*(═NH); wherein L is bonded to the N-terminal nitrogen of X5 at the atom marked with an asterisk (*) and R3 is selected from: H, D, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C9)cycloalkyl, 5-10 membered heterocycloalkyl, aryl, aryloxy, heteroaryloxy, aralkyl, heteroaryl, and heteroaralkyl; wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, aryloxy, heteroaryloxy, aralkyl, heteroaryl, and heteroaralkyl are optionally and independently substituted; T is a lipophilic tether moiety bonded to L; and R1 is OR2 or N(R2)2, each R2 is independently H or alkyl,
wherein at least sixteen contiguous X5-X21 amino acid residues are present, and wherein:X5 is a glycine residue, a methyl serine residue, a homoserine residue, a propargyl glycine residue or a cysteine residue,X6 is a glycine residue,X7 is a tyrosine residue,X8 is a glutamine residue,X9 is a lysine residue,X10 is a lysine residue,X11 is a leucine residue, a proline residue, a photoleucine, a histidine, or a d-leucine,X12 is an arginine residue,X13 is a d-proline residue,X14 is an alanine residue, a homoserine residue, a histidine residue a methyl serine residue, a proline residue, a Dpr residue, a methionine residue, a tryptophan residue, a hydroxyproline residue, or a d-proline residue,X15 is a threonine residue or a histidine residue,X16 is an aspartic acid residue or a threonine residueX17 is a lysine residue,X18 is a tyrosine residue,X19 is an arginine residue,X20 is a leucine residue,X21 is a histidine residue or a leucine residue or absent. |
