BETIDAMINO ACIDS - VERSATILE AND CONSTRAINED SCAFFOLDS FOR DRUG DISCOVERY

Betidamino acids (a contraction of ''beta'' position and ''amide'') ar e N'-monoacylated (optionally, N'-monoacylated and N-mono- or N,N'-dia lkylated) aminoglycine derivatives in which each N'-acyl/alkyl group m ay 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 acylati on of one of the two amino functions of orthogonally protected aminogl ycine(s) to generate the side chain either prior to or after the elong ation of the main chain, We have used unresolved utyloxycarbonyl-N'(al pha)-fluorenylmethoxycarbonyl aminoglycine, and N-alpha-(N-alpha-methy l) utyloxycarbonyl-N'(alpha)-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-NH2, wher e 2Nal is 2-naphthylalanine, 4Cpa is 4-chlorophenylalanine, 3Pal is 3- pyridylalanine, Aph is 4-aminophenylanine, and IIyis is N-epsilon-isop ropyllysine], a potent gonadotropin-releasing hormone antagonist, In o rder to test biocompatibility of these derivatives, Diastereomeric pep tides could be separated in most cases by reverse-phase HPLC. Biologic al results indicated small differences in relative potencies (<5-fold) between the D and L nonalkylated betidamino acid-containing Acyline d erivatives, Importantly, most betide diastereomers were equipotent wit h Acyline, In an attempt to correlate structure and observed potency, Ramachandran-type plots were calculated for a series of betidamino aci ds and their methylated homologs, According to these calculations, bet idamino acids have access to a more limited and distinct number of con formational states (including those associated with alpha-helices, bet a-sheets, or turn structures), with deeper minima than those observed for natural amino acids.