title: Novel analogues of degarelix incorporating hydroxy-, methoxy-, and pegylated-urea moieties at positions 3, 5, 6 and the N-terminus. Part III.
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.
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Samant
authors.forename: Doley J
authors.initials: DJ
authors.lastname: Hong
authors.forename: Glenn
authors.initials: G
authors.lastname: Croston
authors.forename: Catherine
authors.initials: C
authors.lastname: Rivier
authors.forename: Jean
authors.initials: J
authors.lastname: Rivier
mesh_terms: D000215:Acylation; D000818:Animals; D020148:Butyric Acid / Q000737:chemistry*; D002210:Caprylates / Q000737:chemistry*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D005260:Female; D017930:Genes, Reporter; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000097:blood; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009919:Orchiectomy; D010060:Ovulation / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry*
chemical_list: D002210:Caprylates; D009842:Oligopeptides; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D020148:Butyric Acid; D007987:Gonadotropin-Releasing Hormone; D011092:Polyethylene Glycols; D014508:Urea; C031492:octanoic acid