GnRH Antagonists:  A New Generation of Long Acting Analogues Incorporating p-Ureido-phenylalanines at Positions 5 and 6

A series of antagonists of gonadotropin-releasing hormone (GnRH) of the general formula Ac-d2Nal-d4Cpa-d3Pal-Ser-4Aph/4Amf(P)-d4Aph/d4Amf(Q)-Leu-ILys-Pro-dAla-NH2 was synthesized, characterized, and screened for duration of inhibition of luteinizing hormone release in a castrated male rat assay. Sel...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2001-02, Vol.44 (3), p.453-467
Main Authors: Jiang, Guangcheng, Stalewski, Jacek, Galyean, Robert, Dykert, John, Schteingart, Claudio, Broqua, Pierre, Aebi, Audrey, Aubert, Michel L, Semple, Graeme, Robson, Peter, Akinsanya, Karen, Haigh, Robert, Riviere, Pierre, Trojnar, Jerzy, Junien, Jean Louis, Rivier, Jean E
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Line
Drug Evaluation, Preclinical
Gels
Genes, Reporter
Gonadotropin-Releasing Hormone - antagonists & inhibitors
Histamine Release - drug effects
Hormones. Endocrine system
Humans
Luteinizing Hormone - blood
Male
Mast Cells - metabolism
Medical sciences
Oligopeptides - chemical synthesis
Oligopeptides - chemistry
Oligopeptides - pharmacology
Orchiectomy
Pharmacology. Drug treatments
Phenylalanine - analogs & derivatives
Phenylalanine - chemical synthesis
Phenylalanine - chemistry
Phenylalanine - pharmacology
Rats
Rats, Sprague-Dawley
Solubility
Structure-Activity Relationship
Testosterone - blood
Urea - analogs & derivatives
Urea - chemical synthesis
Urea - chemistry
Urea - pharmacology
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Summary:A series of antagonists of gonadotropin-releasing hormone (GnRH) of the general formula Ac-d2Nal-d4Cpa-d3Pal-Ser-4Aph/4Amf(P)-d4Aph/d4Amf(Q)-Leu-ILys-Pro-dAla-NH2 was synthesized, characterized, and screened for duration of inhibition of luteinizing hormone release in a castrated male rat assay. Selected analogues were tested in a reporter gene assay (IC50 and pA2) and an in vitro histamine release assay. P and Q contain urea/carbamoyl functionalities designed to increase potential intra- and intermolecular hydrogen bonding opportunities for structural stabilization and peptide/receptor interactions, respectively. These substitutions resulted in analogues with increased hydrophilicity and a lesser propensity to form gels in aqueous solution than azaline B [Ac-d2Nal-d4Cpa-d3Pal-Ser-4Aph(Atz)-d4Aph(Atz)-Leu-ILys-Pro-dAla-NH2 with Atz = 3‘-amino-1H-1‘,2‘,4‘-triazol-5‘-yl, 5], and in some cases they resulted in a significant increase in duration of action after subcutaneous (sc) administration. Ac-d2Nal-d4Cpa-d3Pal-Ser-4Aph(l-hydroorotyl)-d4Aph(carbamoyl)-Leu-ILys-Pro-dAla-NH2 (acetate salt is FE200486) (31) and eight other congeners (20, 35, 37, 39, 41, 45−47) were identified that exhibited significantly longer duration of action than acyline [Ac-d2Nal-d4Cpa-d3Pal-Ser-4Aph(Ac)-d4Aph(Ac)-Leu-ILys-Pro-dAla-NH2] (6) when administered subcutaneously in castrated male rats at a dose of 50 μg in 100 μL of phosphate buffer. No correlation was found between retention times on a C18 reverse phase column using a triethylammonium phosphate buffer at pH 7.0 (a measure of hydrophilicity) or affinity in an in vitro human GnRH report gene assay (pA2) and duration of action. FE200486 was selected for preclinical studies, and some of its properties were compared to those of other clinical candidates. In the intact rat, ganirelix, abarelix, azaline B, and FE200486 inhibited plasma testosterone for 1, 1, 14, and 57 days, respectively, at 2 mg/kg sc in 5% mannitol (injection volume = 20 μL). Based on the information that 31, 33, 35 and 37 were significantly shorter acting than acyline or azaline B after intravenous administration (100 μg/rat), we surmised that the very long duration of action of the related FE200486 (for example) was likely due to unique physicochemical properties such as solubility in aqueous milieu, comparatively low propensity to form gels, and ability to diffuse at high concentrations in a manner similar to that described for slow release formulations of pep
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0003900