Discovery of 4-[3-(trans-3-Dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]- (4S)-oxazolidin-2-one (4991W93), a 5HT1B/1D Receptor Partial Agonist and a Potent Inhibitor of Electrically Induced Plasma Extravasation

Utilizing a pharmacophoric model of binding of 3-(2-aminoethyl)indoles to 5HT1B/1D receptors, we identified the 3-aminocyclobutyl group as a potential ethylamine isostere. A novel multidimensional chemometric approach was used to predict the intrinsic activity (degree of agonism) at the receptor. A qualitative model for pharmacokinetic properties was then used to guide the synthesis toward molecules likely to have oral bioavailability in humans. A novel synthetic route to 3-(3-dimethylaminocyclobutyl)indoles was developed. Analogues showed generally lower intrinsic activity at 5HT1B/1D receptors than their ethylamine counterparts. 4-[3-(trans-3-Dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93, 1) was identified as a partial agonist against 5HT1B/1D receptors, with low intrinsic activity. This molecule also has significant activity against 5HT1F receptors but is selective over other 5HT receptors. In addition this compound was found to be an exceptionally potent inhibitor of ele...