Novel analogues of degarelix incorporating hydroxy- methoxy- and pegylated-urea moieties at positions 3 5 6 and the N-terminus

摘要

Novel degarelix () 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. N^ω-hydroxy- and N^ω-methoxy-carbamoylation of Dab and Dap at position 3 (>3->6), and N^ω-hydroxy-, N^ω-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.