Helal Christopher J, Kang Zhijun, Lucas John C, Gant Thomas, Ahlijanian Michael K, Schachter Joel B, Richter Karl E G, Cook James M, Menniti Frank S, Kelly Kristin, Mente Scot, Pandit Jay, Hosea Natalie
Neuroscience Medicinal Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Bioorg Med Chem Lett. 2009 Oct 1;19(19):5703-7. doi: 10.1016/j.bmcl.2009.08.019. Epub 2009 Aug 8.
Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.
利用基于结构的药物设计，合成了一种4-氨基咪唑杂环核心，以替代2-氨基噻唑，因为其存在潜在的代谢介导毒性。所采用的合成路线便于1-取代-4-氨基咪唑的合成。通过构效关系研究，鉴定出一种新型的顺式取代环丁基，它对cdk5/p25具有更高的酶活性和细胞活性，对cdk2/细胞周期蛋白E的选择性高达30倍。
