化学
联苯
立体化学
吡唑
双环分子
结构-活动关系
化学合成
组合化学
体外
生物化学
有机化学
作者
Jennifer X. Qiao,Daniel L. Cheney,Richard Alexander,Angela Smallwood,Sarah R. King,Kan He,Alan R. Rendina,Joseph M. Luettgen,Robert M. Knabb,Ruth R. Wexler,Patrick Y.S. Lam
标识
DOI:10.1016/j.bmcl.2008.05.095
摘要
Ortho-substituted biphenyl moieties are widely used in drug design. We herein report a successful use of the perpendicular conformation of the alpha-substituted phenylcyclopropyl groups to mimic the aplanar, biologically active conformation of the ortho-substituted biphenyl moieties to achieve structural diversity. This is exemplified by the design and synthesis of a series of highly potent pyrazole bicyclic-based Factor Xa (FXa) inhibitors bearing alpha-substituted phenylcyclopropyl P4 moieties. The designed perpendicular conformation was confirmed by the X-ray structure of FXa-bound compound 2r. The potential structural basis for the high FXa potency in the phenylcyclopropyl P4 analogs and their improved FXa inhibitory activities compared with the biphenyl P4 counterparts are discussed.
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