Discovery of 4-[3-(trans-3-Dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]- (4S)-oxazolidin-2-one (4991W93), a 5HT_1B/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 5HT_1B/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 5HT_1B/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 5HT_1B/1D receptors, with low intrinsic activity. This molecule also has significant activity against 5HT_1F receptors but is selective over other 5HT receptors. In addition this compound was found to be an exceptionally potent inhibitor of electrically induced plasma extravasation. Compound 1 may have utility in the treatment and prophylaxis of migraine.