Goudreau Nathalie, Cameron Dale R, Déziel Robert, Haché Bruno, Jakalian Araz, Malenfant Eric, Naud Julie, Ogilvie William W, O'meara Jeff, White Peter W, Yoakim Christiane
Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Que., Canada H7S 2G5.
Bioorg Med Chem. 2007 Apr 1;15(7):2690-700. doi: 10.1016/j.bmc.2007.01.036. Epub 2007 Jan 24.
We have previously reported the discovery and initial SAR optimization of the first series of inhibitors of the human papillomavirus type-11 (HPV11) E1-E2 protein-protein interaction. These inhibitors featured an indandione system spiro-fused onto an all syn substituted tetrahydrofuran ring. In this paper, we report new SAR efforts which have led to the identification of the first low nanomolar inhibitor of the HPV11 E1-E2 protein-protein interaction. In addition, we report a combined NMR and computational chemistry approach which allowed the successful determination of the absolute stereochemistry of the active species originating from the initial racemic lead.
我们之前报道了人乳头瘤病毒11型（HPV11）E1-E2蛋白-蛋白相互作用的首个系列抑制剂的发现及初步的构效关系优化。这些抑制剂具有一个与全顺式取代的四氢呋喃环螺稠合的茚二酮体系。在本文中，我们报道了新的构效关系研究工作，这些工作导致了首个低纳摩尔浓度的HPV11 E1-E2蛋白-蛋白相互作用抑制剂的鉴定。此外，我们报道了一种结合核磁共振（NMR）和计算化学的方法，该方法成功确定了源自最初外消旋先导化合物的活性物质的绝对立体化学结构。
