GnRH antagonists: a new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6

Autor: Robert Haigh, Pierre Riviere, Jacek Stalewski, Audrey Aebi, Claudio D. Schteingart, Robert Galyean, Pierre Broqua, Jerzy Trojnar, Graeme Semple, Guangcheng Jiang, Jean Louis Junien, Peter A. Robson, John Dykert, Michel L. Aubert, Karen O. Akinsanya, Jean Rivier
Jazyk: angličtina
Rok vydání: 2001
Předmět:
Male
medicine.medical_specialty
Mast Cells/metabolism
Phenylalanine
Drug Evaluation
Preclinical
Histamine Release
Abarelix
Cell Line
Gonadotropin-Releasing Hormone
Rats
Sprague-Dawley
chemistry.chemical_compound
Structure-Activity Relationship
Urea/analogs & derivatives/chemical synthesis/chemistry/pharmacology
Gonadotropin-Releasing Hormone/antagonists & inhibitors
Genes
Reporter
Internal medicine
Drug Discovery
medicine
Urea
Animals
Humans
Testosterone
Mast Cells
Ganirelix
Receptor
IC50
ddc:613
ddc:618
Phenylalanine/analogs & derivatives/chemical synthesis/chemistry/pharmacology
Antagonist
Histamine Release/drug effects
Luteinizing Hormone
Rats
Endocrinology
chemistry
Solubility
Molecular Medicine
Luteinizing Hormone/blood
Luteinizing hormone
Oligopeptides
Gels
Oligopeptides/chemical synthesis/chemistry/pharmacology
Orchiectomy
Testosterone/blood
Histamine
medicine.drug
Zdroj: Journal of Medicinal Chemistry, Vol. 44, No 3 (2001) pp. 453-67
ISSN: 0022-2623
Popis: 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 (s.c.) 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 microg in 100 microL 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 s.c. in 5% mannitol (injection volume = 20 microL). Based on the information that 31, 33, 35 and 37 were significantly shorter acting than acyline or azaline B after intravenous administration (100 microg/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 peptides. Indeed, in rats injected s.c. with FE200486 (2 mg/kg), plasmatic concentrations of FE200486 remained above 5 ng/mL until day 41, and the time after which they dropped below 3 ng/mL and plasma LH levels started rising until full recovery was reached at day 84 with levels of FE200486 hovering around 1 ng/mL. Additionally, FE200486 was less potent at releasing histamine from isolated rat mast cells than any of the GnRH antagonists presently described in preclinical reports.
Databáze: OpenAIRE
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