Discovery and evaluation of a series of 3-acylindole imidazopyridine platelet-activating factor antagonists

被引：34

作者：

Curtin, ML ^{[1
]}

Davidsen, SK ^{[1
]}

Heyman, HR ^{[1
]}

Garland, RB ^{[1
]}

Sheppard, GS ^{[1
]}

Florjancic, AS ^{[1
]}

Xu, LH ^{[1
]}

Carrera, GM ^{[1
]}

Steinman, DH ^{[1
]}

Trautmann, JA ^{[1
]}

Albert, DH ^{[1
]}

Magoc, TJ ^{[1
]}

Tapang, P ^{[1
]}

Rhein, DA ^{[1
]}

Conway, RG ^{[1
]}

Luo, GJ ^{[1
]}

Denissen, JF ^{[1
]}

Marsh, KC ^{[1
]}

Morgan, DW ^{[1
]}

Summers, JB ^{[1
]}

机构：

[1] Abbott Labs, Div Pharmaceut Prod, Immunosci Res Area, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 01期

关键词：

D O I：

10.1021/jm970389+

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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, 22m.HCl) which has been evaluated extensively and is currently in clinical development.

引用

页码：74 / 95

页数：22

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