Portal de Periódicos da CAPES

Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1

2020; Elsevier BV; Volume: 28; Issue: 10 Linguagem: Inglês

10.1016/j.bmc.2020.115481

1464-3391

Andrew Fensome, Catherine M. Ambler, Eric P. Arnold, Mary Ellen Banker, James D. Clark, Martin E. Dowty, Ivan Efremov, Andrew C. Flick, Brian S. Gerstenberger, Roger S. Gifford, Ariamala Gopalsamy, Martin Hegen, Jason Jussif, David C. Limburg, Tsung H. Lin, Betsy S. Pierce, Raman Sharma, John I. Trujillo, F.F. Vajdos, Fabien Vincent, Zhao‐Kui Wan, Li Xing, Xiaojing Yang, Xin Yang,

interferon and immune responses

Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.