Discovery of 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93), a 5HT(1B/1D) receptor partial agonist and apotent inhibitor of electrically induced plasma extravasation

Utilizing a pharmacophoric model of binding of 3-(2-aminoethyl)indoles to 5 HT(1B/1D) receptors, we identified the 3-aminocyclobutyl group as a potenti al ethylamine isostere. A novel multidimensional chemometric approach was u sed to predict the intrinsic activity (degree of agonism) at the receptor. A qualitative model for pharmacokinetic properties was then used to guide t he synthesis toward molecules likely to have oral bioavailability in humans . A novel synthetic route to 3-(3-dimethylaminocyclobutyl)indoles was devel oped. Analogues showed generally lower intrinsic activity at 5HT1B/1D recep tors than their ethylamine counterparts. 4-[3-(trans-3-Dimethylaminocyclobu tyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93, 1) was identified as a partial agonist against 5HT1B/1D receptors, with low intrinsic activi ty. This molecule also has significant activity against 5HT(1F) receptors b ut is selective over other 5HT receptors. In addition this compound was fou nd to be an exceptionally potent inhibitor of electrically induced plasma e xtravasation. Compound 1 may have utility in the treatment and prophylaxis of migraine.