1. Antagonists of the luteinizing hormone releasing hormone with pyridyl-alanines which completely inhibit ovulation at nanogram dosage
K Folkers, C Y Bowers, T Kubiak, J Stepinski Biochem Biophys Res Commun. 1983 Mar 29;111(3):1089-95. doi: 10.1016/0006-291x(83)91411-0.
[N-Ac-D-2-Nal1,pCl-D-Phe2,D-3-Pal3,D-Arg6,D-Ala10]-LHRH caused 100% and 57% inhibition of ovulation in rats, s.c., at 500 and 250 ng, respectively, and 56%, per os at 500 micrograms. [N-Ac-3,4-diC1-D-Phe1,pC1-D-Phe2,D-3-Pal3,D-Arg6,D-Ala10]-LHRH inhibited ovulation, s.c., 82% at 500 ng, and 63%, per os at 500 micrograms. These analogs are the most effective reported inhibitors of ovulation. The new introduction of pyridyl-alanines can be superior substituents. For pairs of analogs, relationships are: D-3-Pal (beta-(3-pyridyl)-D-alpha-alanine) in position 3 is superior to D-Trp3, D-2-Pal3 and D-4-Pal3. D-Arg6 was superior to D-3-Pal6 and D-4-Pal6 was superior by 2-fold to D-Arg6. D-Ala10 was superior to Gly10 and D-Abu10.
2. Synthesis of 3-(3-pyridyl)- and 3-(3-benzo[b]thienyl)-D-alanine
P N Rao, J E Burdett Jr, J W Cessac, C M DiNunno, D M Peterson, H K Kim Int J Pept Protein Res. 1987 Jan;29(1):118-25. doi: 10.1111/j.1399-3011.1987.tb02237.x.
The DL-arylamino acid ethyl ester derivatives of beta-(3-pyridyl)-DL-alanine, and beta-(3-benzo[b]thienyl)-DL-alanine were synthesized by diethyl acetamidomalonate condensation with the respective arylmethyl halides followed by partial hydrolysis to the monoethyl ester and decarboxylation. Each derivative was enzymatically resolved to a separable mixture of the corresponding N-acetyl-L-amino acid and the unchanged D amino acid derivative. Acidic hydrolysis of the latter gave the corresponding D-amino acid, the optical purity of which was established by HPLC analysis of the 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC) derivative. The free D amino acids were converted to D-BOC derivatives by reaction with di-tert-butyldicarbonate in tert-butyl alcohol, water and sodium hydroxide.
