138925-46-9Relevant academic research and scientific papers
Synthesis of indole oxazolines, potent 5-HT3 antagonists
Swain, Christopher J.,Kueen, Clare,Baker, Raymond
, p. 2445 - 2448 (1990)
The synthesis of a series of indole oxazolines is reported, proceding via addition of an azabicyclic amino alcohol, in which the azacyclic nitrogen is borane protected, to an indole imidate. Selective alkylation of the indole nitrogen is facilitated by the borane protection of the highly nucleophilic azabicyclic nitrogen.
Novel 5-HT3 antagonists: Indol-3-ylspiro(azabicycloalkane-3,5'(4'H)- oxazoles)
Swain,Baker,Kneen,Herbert,Moseley,Saunders,Seward,Stevenson,Beer,Stanton,Watling,Ball
, p. 1019 - 1031 (2007/10/02)
The synthesis and biochemical evaluation of a series of spirofused indole oxazoline 5-HT3 antagonists is described in which the oxazoline ring acts as a bioisosteric replacement for esters and amides. The effect of substitution about the indole ring has shown the steric limitations of the aromatic binding site. Incorporation of a variety of azabicyclic systems within the rigid spirofused framework has allowed the definition of a binding model which incorporates a number of known antagonists and agonists. In this model steric constraints limit substitution around the indole ring although there is some bulk tolerance at the 1- and 2-positions. The importance of constraining the basic nitrogen within an azabicyclic system is underlined by comparison with the monocyclic piperidine. The highest affinity was observed for those compounds in which the basic nitrogen occupies a bridgehead position, the most potent analogue in this group being the azabicyclic [3.3.1] system (pIC50 = 8.95), suggesting lipophilic interactions may play a role in increasing affinity. A suggested model for agonist binding is included in which the basic nitrogens are superimposed and the 5-hydroxyl group of 5-HT is superimposed on the H-bond-accepting atom of the heterocyclic linking group.
