Betidamino acid scan of the GnRH antagonist acyline

摘要: Strong clinical evidence suggests that GnRH antagonists will replace agonists in a number of indications because their ability to inhibit gonadotropin secretion as long an adequate concentration the analogue is present circulation whereas superagonists take approximately 2 weeks desensitize gonadotrophs. Until recently, were either too weak and/or would release histamine. Azaline B {[Ac-D2Nal1,D4Cpa2,D3Pal3, 4Aph5(atz),D4Aph6(atz),ILys8,DAla10] GnRH} and long-acting members azaline family {Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(X)-D4Aph(Y) -Leu-ILys-Pro-DAla-NH2}, however, appear be promising drug candidates. Because these tend form gels (due formation beta-sheet structures) and, result, are not readily amenable formulation for long-term delivery, we have investigated ways increasing hydrophilicity while retaining high potency lack histamine releasing activity. Betidamino acids (a contraction "beta" position "amide") N'-monoacylated (optionally, N-mono- or N,N'-dialkylated) aminoglycine derivatives which each N'-acyl/alkyl group may mimic naturally occurring amino acid side chains introduce novel functionalities. We used unresolved N alpha-Boc,N'alpha-Fmoc-aminoglycine, alpha-Boc,N'alpha-(CH3)Fmoc-aminoglycine templates introduction betidamino acyline (Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(A c)-Leu-Ilys-Pro-DAla-NH2), acting member family, test biocompatibility betide derivatives. Diastereomeric peptides could separated using RP-HPLC most cases. Biological results obtained vitro (binding affinity rat pituitary gland membranes) vivo (rat antiovulatory assay, AOA) indicate cases small differences relative potencies (< 5-fold) between D- L-nonalkylated acid-containing acylines. Importantly, diastereomers receptor equipotent with AOA. Greater observed after methyl on chain nitrogen ("beta" position) same analogues, one diastereomer having AOA equivalent acyline. These suggest chirality at alpha-carbon coupled orientation important recognition. The duration action some potent analogues was also determined castrated male order measure extent (efficacy action) inhibition luteinizing hormone release. Data reduction action. Also, increased (as by elution times C18 silicas pH 7.3) compared parent compound. N'-Methyl substitution parallel increase retention expected.