Liu Jiwen, Fu Zice, Li An-Rong, Johnson Michael, Zhu Liusheng, Marcus Andrew, Danao Jay, Sullivan Tim, Tonn George, Collins Tassie, Medina Julio
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2009 Sep 1;19(17):5114-8. doi: 10.1016/j.bmcl.2009.07.032. Epub 2009 Jul 10.
The evaluation of the CXCR3 antagonist AMG 487 in clinic trials was complicated due to the formation of an active metabolite. In this Letter, we will discuss the further optimization of the quinazolinone series that led to the discovery of compounds devoid of the formation of the active metabolite that was seen with AMG 487. In addition, these compounds also feature increased potency and good pharmacokinetic properties. We will also discuss the efficacy of the lead compound 34 in a mouse model of cellular recruitment induced by bleomycin.
由于活性代谢物的形成，CXCR3拮抗剂AMG 487在临床试验中的评估变得复杂。在本信函中，我们将讨论喹唑啉酮系列的进一步优化，该优化导致发现了不会形成如AMG 487所见活性代谢物的化合物。此外，这些化合物还具有增强的效力和良好的药代动力学性质。我们还将讨论先导化合物34在博来霉素诱导的细胞募集小鼠模型中的疗效。
