Kempson James, Spergel Steven H, Guo Junqing, Quesnelle Claude, Gill Patrice, Belanger Dominique, Dyckman Alaric J, Li Tianle, Watterson Scott H, Langevine Charles M, Das Jagabandhu, Moquin Robert V, Furch Joseph A, Marinier Anne, Dodier Marco, Martel Alain, Nirschl David, Van Kirk Katy, Burke James R, Pattoli Mark A, Gillooly Kathleen, McIntyre Kim W, Chen Laishun, Yang Zheng, Marathe Punit H, Wang-Iverson David, Dodd John H, McKinnon Murray, Barrish Joel C, Pitts William J
Departments of Discovery Chemistry, Discovery Biology, and Metabolism and Pharmacokinetics and Synthesis and Analysis Technology Team, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543-4000, USA.
J Med Chem. 2009 Apr 9;52(7):1994-2005. doi: 10.1021/jm8015816.
The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.
报道了一系列新型基于恶唑、噻唑和咪唑的IkappaB激酶（IKK）抑制剂的设计与合成。与吡唑并嘌呤先导化合物相比，其生物活性得到了提高，并且新三环体系的便捷合成使得能够高效地探索构效关系。这与迭代大鼠灌胃给药策略相结合，用于鉴定具有改善药代动力学（PK）特征的化合物，以推进体内评价。
