Novel Analogues of Degarelix Incorporating Hydroxy-, Methoxy-, and Pegylated-Urea Moieties at Positions 3, 5, 6 and the N-Terminus. Part III

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Abstract
Novel degarelix (Fe200486) analogues were screened for antagonism of GnRH-induced response (IC50) in a reporter gene assay. Inhibition of luteinizing hormone release over time was measured in the castrated male rat. Nω-Hydroxy- and Nω-methoxy-carbamoylation of Dab and Dap at position 3 (3−6), and Nω-hydroxy-,Nω-methoxy-carbamoylation and pegylation of 4Aph at positions 5 and 6 (7 − 10, 15 − 17, 22 − 25) were carried out. Modulation of hydrophobicity was achieved using different acylating groups at the N-terminus (11 − 14, 18 − 21, 26 − 28). Analogues 8, 15 − 17, 22, and 23 were equipotent to acyline (IC50 = 0.69 nM) and degarelix (IC50 = 0.58 nM) in vitro. Analogues 7, 17, and 23 were shorter acting than acyline, when 9, 11, 13, 15, 16, and 22 were longer acting. Only 9 and 14 were inactive at releasing histamine. No analogue exhibited a duration of action comparable to that of degarelix. Analogues with shorter and longer retention times on HPLC (a measure of hydrophilicity) than degarelix were identified.