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. published an article on February 1 ,2001. The article was titled 《GnRH Antagonists: A New Generation of Long Acting Analogues Incorporating p-Ureido-phenylalanines at Positions 5 and 6》, and you may find the article in Journal of Medicinal Chemistry.HPLC of Formula: 324017-21-2 The information in the text is summarized as follows:
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 LH release in a castrated male rat assay. Selected analogs 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 intermol. hydrogen bonding opportunities for structural stabilization and peptide/receptor interactions, resp. These substitutions resulted in analogs 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; Atz = 3′-amino-1H-1′,2′,4′-triazol-5′-yl], and in some cases they resulted in a significant increase in duration of action after s.c. administration. Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(L-hydroorotyl)-D4Aph(carbamoyl)-Leu-ILys-Pro-DAla-NH2 (acetate salt is FE200486) (I) 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 s.c. 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. I was selected for preclin. studies, and some of its properties were compared to those of other clin. candidates. In the intact rat, ganirelix, abarelix, azaline B, and I inhibited plasma testosterone for 1, 1, 14, and 57 days, resp., at 2 mg/kg s.c. in 5% mannitol (injection volume = 20 μL). Based on the information that I, 33, 35 and 37 were significantly shorter acting than acyline or azaline B after i.v. administration (100 μg/rat), we surmised that the very long duration of action of the related I (for example) was likely due to unique physicochem. 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 I (2 mg/kg), plasmatic concentrations of I 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 I hovering around 1 ng/mL. Addnl., I was less potent at releasing histamine from isolated rat mast cells than any of the GnRH antagonists presently described in preclin. reports. In the experiment, the researchers used many compounds, for example, Fmoc-D-Phe(4-NH2)-OH(cas: 324017-21-2HPLC of Formula: 324017-21-2)
Fmoc-D-Phe(4-NH2)-OH(cas: 324017-21-2) belongs to ethers.HPLC of Formula: 324017-21-2Although ethers resist hydrolysis, they are cleaved by hydrobromic acid and hydroiodic acid. Hydrogen chloride cleaves ethers only slowly.
Referemce:
Ether – Wikipedia,
Ether | (C2H5)2O – PubChem