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

J Med Chem. 2006 Jun 15;49(12):3536-43. doi: 10.1021/jm060240a.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acylation
  • Animals
  • Butyric Acid / chemistry*
  • Caprylates / chemistry*
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Female
  • Genes, Reporter
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors
  • Gonadotropin-Releasing Hormone / blood
  • Histamine Release / drug effects
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Male
  • Mast Cells / drug effects
  • Mast Cells / metabolism
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Orchiectomy
  • Ovulation / drug effects
  • Polyethylene Glycols / chemistry*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Urea / chemistry*

Substances

  • Caprylates
  • Oligopeptides
  • acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide
  • Butyric Acid
  • Gonadotropin-Releasing Hormone
  • Polyethylene Glycols
  • Urea
  • octanoic acid