Trujillo John I, Huang Horng-Chih, Neumann William L, Mahoney Matthew W, Long Scott, Huang Wei, Garland Danny J, Kusturin Carrie, Abbas Zaheer, South Michael S, Reitz David B
Department of Medicinal Chemistry, Pfizer Global Research and Development, Chesterfield, MO 63017, USA.
Bioorg Med Chem Lett. 2007 Aug 15;17(16):4568-74. doi: 10.1016/j.bmcl.2007.05.090. Epub 2007 Jun 6.
Herein is described the design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors were designed to explore replacement and variation of the P1 amidine described previously [J. Med. Chem.2003, 46, 4050]. The P1 needle replacements were selected based upon their reduced basicity compared to the parent phenyl amidine (pKa approximately 12). A contributing factor towards the oral bioavailability of a compound is the ionization state of the compound in the intestinal tract. The desired outcome of the study was to identify an orally bioavailable TF-VIIa inhibitor.
本文描述了一系列取代吡嗪酮作为组织因子/因子VIIa复合物抑制剂的设计、合成及酶活性。这些抑制剂旨在探索先前所述P1脒的替代和变化[《药物化学杂志》2003年，46卷，4050页]。基于与母体苯基脒相比碱性降低（pKa约为12）来选择P1针状取代物。化合物口服生物利用度的一个促成因素是该化合物在肠道中的离子化状态。该研究的预期结果是鉴定出一种口服生物可用的组织因子-因子VIIa抑制剂。
