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J Med Chem. 2006 Jun 15;49(12):3536-43.

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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1
The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, California 92037, USA.

Abstract

Novel degarelix (Fe200486) analogues were screened for antagonism of GnRH-induced response (IC(50)) 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 (IC(50) = 0.69 nM) and degarelix (IC(50) = 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.

PMID:
16759096
PMCID:
PMC2536684
DOI:
10.1021/jm060240a
[Indexed for MEDLINE]
Free PMC Article

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