Fluorinated GHRH antagonists
Inventors
Schally, Andrew • Varga, Jozsef • Zarandi, Marta • Cai, Ren Zhi
Assignees
University of Miami • US Department of Veterans Affairs
Publication Number
US-8227405-B2
Publication Date
2012-07-24
Expiration Date
2029-09-17
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Abstract
Novel fluorinated synthetic analogs of hGH-RH(1-30)NH2 that inhibit the release of growth hormone from the pituitary in mammals as well as inhibit the proliferation of human cancers through a direct effect on the cancer cells, and to therapeutic compositions containing these novel peptides and their use.
Core Innovation
The invention relates to novel fluorinated synthetic analogs of hGH-RH(1-30)NH2 that inhibit the release of growth hormone from the pituitary in mammals and also inhibit the proliferation of human cancers through a direct effect on the cancer cells. These analogs have enhanced inhibitory potencies compared to previously described analogs, which result from the replacement of various amino acids, particularly involving di- or poly-fluorinated phenylalanine substitutions in specific positions.
The problem being addressed is the limited knowledge and lack of effective GH-RH analogs that exert direct antagonistic effects on tumor cells expressing GH-RH receptors different from those found in the pituitary. Existing GH-RH antagonists, although useful in lowering serum GH and IGF-I levels, do not have well-characterized structure-activity relationships for direct tumor inhibition, and more potent analogs are required for clinical efficacy in diseases such as acromegaly, diabetic retinopathy, diabetic nephropathy, and various cancers.
Claims Coverage
The patent includes one principal independent claim defining a novel peptide with specific structural formulae. The main inventive features include detailed structural modifications, especially the incorporation of fluorinated substituents and defined amino acid residues in the peptide sequence.
Fluorinated synthetic analog peptide structure
A peptide selected from specified formulae of hGH-RH(1-30)NH2 analogs having N-terminal substituents that include mono- or poly-fluorinated phenylacetic or phenylpropionic acid derivatives and other carboxyl groups, incorporating specific amino acid residues at defined positions with fluorinated phenylalanine and other modified amino acids.
Specific amino acid substitutions and modifications
The peptide features specific residues such as A0 being omega-amino acids or dimers/trimers, A1 as fluorinated phenylalanine or related residues, A2 as D-Arg or equivalents, and critical di- or poly-fluorinated phenylalanine at position A10 and others. Additional residues include ornithine, homoarginine, and non-coded amino acids while maintaining function as GH-RH antagonists.
Pharmaceutical compositions and salt forms
The peptides are provided as pharmaceutically acceptable salts, including pamoate salts exhibiting long duration of activity, formulated for various modes of administration like injections, nasal sprays, inhalation, or depot forms, enabling therapeutic use.
The claims cover novel fluorinated GH-RH analog peptides with defined structural and substitution patterns conferring improved antagonistic activity against GH release and tumor proliferation, as well as pharmaceutical formulations and salts thereof.
Stated Advantages
The new analogs have stronger inhibitory potencies compared to previously described GH-RH antagonists due to specific amino acid replacements, especially fluorinated phenylalanine substitutions.
They inhibit the release of growth hormone and directly inhibit proliferation of human cancers through multiple mechanisms, including endocrine suppression and direct tumor receptor antagonism.
Pharmaceutically acceptable salts of low solubility, such as pamoate salts, provide long duration of activity suitable for effective clinical use.
Documented Applications
Therapeutic use to suppress growth hormone levels and treat conditions associated with excessive growth hormone such as acromegaly, diabetic retinopathy, and diabetic nephropathy.
Treatment of a wide variety of human cancers including lung, prostate, breast, ovary, endometrium, stomach, colon, pancreas, kidney, bone, liver, glioblastomas, pheochromocytomas, melanomas, lymphomas, and others expressing GH-RH, IGF-I/IGF-II, or GH receptors.
Use in benign proliferative disorders like benign prostatic hyperplasia and gynecologic conditions including myoma, endometriosis, and polycystic ovary syndrome.
Inhibition of angiogenesis through reduction of VEGF synthesis, benefiting tumors dependent on neoangiogenesis and vascular growth factors.
Use in prevention or reduction of restenosis in vessels and synthetic stents, particularly post-angioplasty and dialysis, including coating or incorporation of GH-RH antagonists onto devices.
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