Novel, Potent Luteinizing Hormone-Releasing Hormone Antagonists with Improved Solubility in Water

Abstract

A series of luteinizing hormone-releasing hormone antagonists with new substitutions in position 6 or positions 5 and 6 that included lysine acylated at the epsilon-amino group with different heterocyclic carboxylic acids or amino-substituted heterocyclic carboxylic acids was synthesized. These novel analogs wee synthesized on a solid-phase support via the acylation of lysine residue in otherwise protected resin-bound peptides. All analogs were tested in the rat antiovulatory assay (AOA) and the best of them in in vitro histamine release assay. Introduction of lysine acylated with amino-substituted heterocyclic carboxylic acids yielded several water-soluble antagonists with good therapeutic ratio (high AOA to low histamine releasing activity). The best antagonist in terms of activity, histamine release, and solubility was nictide: NAcDNal-DCpa-DPal-Ser-PicLys-D(6ANic)-Orn- Leu-ILys-Pro-DAlaNH2 (6ANic = 6-aminonicotinoyl).

Amino Acid Binding by 2‐(Guanidiniocarbonyl)pyridines in Aqueous Solvents: A Comparative Binding Study Correlating Complex Stability with Stereoelectronic Factors

“…The commercially available 6-methylpyridin-2-ylamine (14) was acylated with acetic anhydride in toluene by a literature procedure. [9] The methyl group of the pyridinium salt 15 was oxidized with KMnO 4 to provide the pyridinecarboxylic acid 16, [9,10] which after activation with PyBOP was coupled with the mono-Boc-protected guanidine 9 to yield the Boc-protected receptor 17. The last step was the deprotection of 17 with TFA and the crystallization of the picrate salt of the receptor 3 from methanol.…”

Chemistry and Molecular Biology in the Search for New LHRH Antagonists

“…Molecular restrictions, such as head-to-tail cyclization, can be accompanied by improved stability and duration of activity in peptides and also in heterocyclic lead structures, if the restriction includes the bioactive conformation (matched core) . [5 21 The same applies to dimerization and partial dimerization through binding of suitable (partial) sequences, for example on the Lys6 side chain, and also for cyclization from the C-terminus to the middle of the molecule. A multitude of cyclopeptides with LHRH sequences have been synthesized which confirm this (see Schemes 3 and 4).…”

A Cyclic Hexapeptide Containing L ‐Proline and 6‐Aminopicolinic Acid Subunits Binds Anions in Water

“…In particular the latter proposal has led to heated and controversial discussions. [7] Very strong homonuclear hydrogen bonds (XÀHÀX) are experimentally well accessible, and numerous examples of centered or almost centered geometries have been reliably found by neutron diffraction experiments. [8] For heteronuclear hydrogen bonds, the structural information is much poorer.…”