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

摘要

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. N-omega-Hydroxy-and N-omega-methoxy-carbamoylation of Dab and Dap at position 3 ( 3-6), and N omega-hydroxy-, N-omega-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.