Palacios Daniel S, Meredith Erik L, Kawanami Toshio, Adams Christopher M, Chen Xin, Darsigny Veronique, Palermo Mark, Baird Daniel, George Elizabeth L, Guy Chantale, Hewett Jeffrey, Tierney Laryssa, Thigale Sachin, Wang Louis, Weihofen Wilhelm A
Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.
Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
ACS Med Chem Lett. 2019 Oct 10;10(11):1524-1529. doi: 10.1021/acsmedchemlett.9b00325. eCollection 2019 Nov 14.
Small molecules that inhibit the metabolic enzyme NAMPT have emerged as potential therapeutics in oncology. As part of our effort in this area, we took a scaffold morphing approach and identified 3-pyridyl azetidine ureas as a potent NAMPT inhibiting motif. We explored the SAR of this series, including 5 and 6 amino pyridines, using a convergent synthetic strategy. This lead optimization campaign yielded multiple compounds with excellent in vitro potency and good ADME properties that culminated in compound .
抑制代谢酶烟酰胺磷酸核糖转移酶（NAMPT）的小分子已成为肿瘤学领域的潜在治疗药物。作为我们在该领域工作的一部分，我们采用了骨架变形方法，并确定3-吡啶基氮杂环丁烷脲为有效的NAMPT抑制基序。我们使用汇聚合成策略探索了该系列的构效关系，包括5-氨基吡啶和6-氨基吡啶。这次先导化合物优化研究产生了多种具有优异体外活性和良好药代动力学性质的化合物，最终得到了化合物。
