Discovery and development of the novel potent orally active thrombin inhibitor N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460):: Coapplication of structure-based design and rapid multiple analogue synthesis on solid support

被引:73
作者
Brady, SF [1 ]
Stauffer, KJ
Lumma, WC
Smith, GM
Ramjit, HG
Lewis, SD
Lucas, BJ
Gardell, SJ
Lyle, EA
Appleby, SD
Cook, JJ
Holahan, MA
Stranieri, MT
Lynch, JJ
Lin, JH
Chen, IW
Vastag, K
Naylor-Olsen, AM
Vacca, JP
机构
[1] Merck Res Labs, Dept Med Chem, W Point, PA 19486 USA
[2] Merck Res Labs, Dept Biol Chem, W Point, PA 19486 USA
[3] Merck Res Labs, Dept Pharmacol, W Point, PA 19486 USA
[4] Merck Res Labs, Dept Drug Metab, W Point, PA 19486 USA
[5] Merck Res Labs, Dept Mol Design & Divers, W Point, PA 19486 USA
关键词
D O I
10.1021/jm9705014
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Early studies in these laboratories of peptidomimetic structures containing a basic P-1 moiety led to the highly potent and selective thrombin inhibitors 2 (K-i = 5.0 nM) and 3 (K-i = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties tia a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P-3 residue is replaced with a range of lipophilic carboxylic amides. Assembly proceeds from the common P-2-P-1 template 7 linked via an acid-labile carbamate to a polystyrene support. Application of the methodology in a repetitive fashion afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460 8, K-i = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 mu g/kg/min, exhibits oral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor 8 has been subject to further evaluation as a possible treatment for thrombogenic disorders.
引用
收藏
页码:401 / 406
页数:6
相关论文
共 11 条