Synthesis of a novel class of heteroaromatic amino acids and their use in the preparation of analogues of luteinizing hormone-releasing hormone.
A novel class of heterocyclic aromatic amino acids based on the 3-(2-benzimidazolyl)alanine system has been generated by chiral synthesis from D- or L-aspartic acid. The use of variously substituted o-phenylenediamines for condensation with the beta-carboxyl function of alpha-benzyl N-(benzyloxycarbonyl)-D-aspartate has led to a series of amino acids of graded hydrophobicity with a steric bulk similar to that of tryptophan. In a similar fashion, we have prepared 3-(2-benzothiazolyl)-D-alanine from o-aminothiophenol and 3-(2-benzoxazolyl)-D-alanine from o-aminophenol. Incorporation of these amino acids into the 6-position of luteinizing hormone-releasing hormone (LH-RH) led to a series of very potent agonist analogues (up to 160 times LH-RH potency), active in doses ranging from 0.1 to 0.5 microgram by twice daily injection in a rat estrus cyclicity suppression assay designed to show the paradoxical antifertility effects of these compounds.
D000409:Alanine / Q000031:analogs & derivatives*; D000818:Animals; D052160:Benzothiazoles; D055598:Chemical Phenomena; D002621:Chemistry; D004971:Estrus / Q000187:drug effects; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D008722:Methods; D011247:Pregnancy; D051381:Rats; D014364:Tryptophan
D052160:Benzothiazoles; D007987:Gonadotropin-Releasing Hormone; C040558:3-(2-benzothiazolyl)alanine; C040557:3-(2-benzimidazolyl)alanine; C040559:3-(2-benzoxazolyl)alanine; D014364:Tryptophan; D000409:Alanine