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.
GlaxoWellcome, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
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Jandu
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Barrett
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Brockwell
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Cambridge
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Farrant
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Foster
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Giles
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Glen
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Hill
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Hobbs
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Honey
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Martin
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Salmon
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Smith
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Woollard
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Selwood
D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D016466:CHO Cells; D002199:Capillary Permeability / Q000187:drug effects*; D002417:Cattle; D006224:Cricetinae; D004423:Ear / Q000098:blood supply; D004558:Electric Stimulation; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013329:Structure-Activity Relationship; D012668:Trigeminal Ganglion / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C423339:4991W93; C470302:HTR1B protein, human; D007211:Indoles; D010080:Oxazoles; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D012710:Serum Albumin, Bovine