Chiral-pool synthesis of 1,2,4-trisubstituted 1,4-diazepanes as novel sigma(1) receptor ligands

Fanter, Lena; Müller, Christoph; Schepmann, Dirk; Bracher, Franz und Wünsch, Bernhard (2017): Chiral-pool synthesis of 1,2,4-trisubstituted 1,4-diazepanes as novel sigma(1) receptor ligands. In: Bioorganic & Medicinal Chemistry, Bd. 25, Nr. 17: S. 4778-4799

Abstract

Starting from enantiomerically pure amino acids, 1,4-diazepanes with various substituents in 1, 2, and 4-position were synthesized following the late stage diversification strategy. The key step in the formation of the seven-membered ring was the intramolecular EDC coupling of amino acids 15, 26, and 39. The configuration in 2-position does not influence the sigma(1) affinity and selectivity over related receptors. A cyclohexylmethyl or a butyl group are the preferred substituents in 4-position, whereas a methyl moiety in 2-position and a (substituted) benzyl moiety in 1-position result in the highest cri affinity. These results fit nicely to the reported cri pharmacophore models. The compounds did not inhibit the structurally related fungal enzyme sterol Delta(8,7)-isomerase, but showed inhibition of diverse enzymes in late cholesterol biosynthesis at high concentrations. In a screening against more than 50 target proteins, (2S)-1-benzyl 4 (4 methoxybenzyl)-2-methyl-1,4-diazepane ((S)-28b, K-i(sigma(1)) = 0.86 nM) showed a clean receptor profile. The dose dependent potentiation of electrically stimulated contractions of guinea pig vas deferens indicates cri agonistic activity of (S)-28b. Even at a dose of 100 mg/kg (S)-28b did not induce severe toxic or behavioral effects in the Irwin screen. Clear cognition enhancing effects were observed for (S)-28b after inducing amnesia by scopolamine.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department für Pharmazie - Zentrum für Pharmaforschung
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 0968-0896
• Sprache: Englisch