Betidamino Acids: Versatile and Constrained Scaffolds for Drug Discovery

Betidamino acids (a contraction of ``beta'' position and ``amide'') are N′-monoacylated (optionally, N′-monoacylated and N-mono- or N,N′-dialkylated) aminoglycine derivatives in which each N′-acyl/alkyl group may mimic naturally occurring amino acid side chains or introduce novel functionalities. Betidamino acids are most conveniently generated on solid supports used for the synthesis of peptides by selective acylation of one of the two amino functions of orthogonally protected aminoglycine(s) to generate the side chain either prior to or after the elongation of the main chain. We have used unresolved Nα-tert-butyloxycarbonyl-N′ α-fluorenylmethoxycarbonyl aminoglycine, and Nα-(Nα-methyl)-tert-butyl oxycarbonyl-N′ α-fluorenylmethoxycarbonyl aminoglycine as the templates for the introduction of betidamino acids in Acyline [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(Ac)-Leu-Ilys-Pro-DAla-NH$_{ 2}$, where 2Nal is 2-naphthylalanine, 4Cpa is 4-chlorophenylalanine, 3Pal is 3-pyridylalanine, Aph is 4-aminophenylalanine, and Ilys is Nε-isopropyllysine], a potent gonadotropin-releasing hormone antagonist, in order to test biocompatibility of these derivatives. Diastereomeric peptides could be separated in most cases by reverse-phase HPLC. Biological results indicated small differences in relative potencies (