Curtin M L, Davidsen S K, Heyman H R, Garland R B, Sheppard G S, Florjancic A S, Xu L, Carrera G M, Steinman D H, Trautmann J A, Albert D H, Magoc T J, Tapang P, Rhein D A, Conway R G, Luo G, Denissen J F, Marsh K C, Morgan D W, Summers J B
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
J Med Chem. 1998 Jan 1;41(1):74-95. doi: 10.1021/jm970389+.
Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.
旨在发现第二代血小板激活因子（PAF）拮抗剂的研究已确定了一类新型的强效口服活性拮抗剂，这类拮抗剂在动物模型中具有高水溶性和长效作用。这些化合物是由雅培第一代PAF拮抗剂ABT - 299（2）的亲脂性吲哚部分与英国生物技术公司的BB - 882（1）的甲基咪唑并吡啶杂环部分组合而成，兼具这两种临床候选药物的积极特性。构效关系（SAR）研究表明，对先导化合物7b的吲哚和苯甲酰间隔基进行修饰可得到活性更强、作用时间更长且生物利用度更高的类似物，并由此确定了1 -（N，N - 二甲基氨基甲酰基）- 4 - 乙炔基 - 3 - [3 - 氟 - 4 - [（1H - 2 - 甲基咪唑并[4,5 - c]吡啶 - 1 - 基）甲基]苯甲酰基]吲哚盐酸盐（ABT - 491，22 m.HCl），该化合物已得到广泛评估，目前正处于临床开发阶段。
