Temple Kayla J, Duvernay Matthew T, Maeng Jae G, Blobaum Anna L, Stauffer Shaun R, Hamm Heidi E, Lindsley Craig W
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2016 Nov 15;26(22):5481-5486. doi: 10.1016/j.bmcl.2016.10.020. Epub 2016 Oct 11.
This letter describes the further deconstruction of the known PAR4 inhibitor chemotypes (MWs 490-525 and with high plasma protein binding) to identify a minimum PAR4 pharmacophore devoid of metabolic liabilities and improved properties. This exercise identified a greatly simplified 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazole scaffold that afforded nanomolar inhibition of both activating peptide and γ-thrombin mediated PAR4 stimulation, while reducing both molecular weight and the number of hydrogen bond donors/acceptors by ∼50%. This minimum PAR4 pharmacophore, with competitive inhibition, versus non-competitive of the larger chemotypes, allows an ideal starting point to incorporate desired functional groups to engender optimal DMPK properties towards a preclinical candidate.
这封信描述了对已知PAR4抑制剂化学类型（分子量为490 - 525且具有高血浆蛋白结合率）的进一步解构，以确定一个没有代谢负担且性质得到改善的最小PAR4药效团。这项工作确定了一个大大简化的2 - 甲氧基 - 6 - 芳基咪唑并[2,1 - b][1,3,4]噻二唑支架，该支架对激活肽和γ - 凝血酶介导的PAR4刺激均具有纳摩尔级抑制作用，同时分子量和氢键供体/受体数量均减少了约50%。这个最小PAR4药效团具有竞争性抑制作用，与较大化学类型的非竞争性抑制不同，它为引入所需官能团以产生针对临床前候选药物的最佳药物代谢动力学性质提供了一个理想的起点。
