Jandu K S, Barrett V, Brockwell M, Cambridge D, Farrant D R, Foster C, Giles H, Glen R C, Hill A P, Hobbs H, Honey A, Martin G R, Salmon J, Smith D, Woollard P, Selwood D L
GlaxoWellcome, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
J Med Chem. 2001 Mar 1;44(5):681-93. doi: 10.1021/jm000956k.
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.
利用3-(2-氨基乙基)吲哚与5HT(1B/1D)受体结合的药效团模型，我们确定3-氨基环丁基为潜在的乙胺电子等排体。采用一种新颖的多维化学计量学方法预测受体的内在活性（激动程度）。然后使用药代动力学性质的定性模型指导合成可能具有人体口服生物利用度的分子。开发了一种合成3-(3-二甲基氨基环丁基)吲哚的新路线。类似物在5HT(1B/1D)受体上的内在活性通常低于其乙胺类似物。4-[3-(反式-3-二甲基氨基环丁基)-1H-吲哚-5-基甲基]-(4S)-恶唑烷-2-酮(4991W93, 1)被确定为针对5HT(1B/1D)受体的部分激动剂，内在活性较低。该分子对5HT(1F)受体也有显著活性，但对其他5HT受体具有选择性。此外，发现该化合物是电诱导血浆外渗的一种极其有效的抑制剂。化合物1可能在偏头痛的治疗和预防中具有应用价值。
